This Phase III, randomized, double-blind, placebo-controlled study will compare the efficacy, safety, and pharmacokinetics of polatuzumab vedotin plus R-CHP versus R-CHOP in participants with previously untreated diffuse large B-cell lymphoma (DLBCL).

Inclusion Criteria:

• Previously untreated participants with cluster of differentiation 20 (CD20)-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms: DLBCL, not otherwise specified (NOS) including germinal center B-cell type, activated B-cell type; T-cell/histiocyte-rich large B-cell lymphoma; Epstein-Barr virus-positive DLBCL, NOS; anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma; human herpesvirus-8 (HHV8)-positive DLBCL, NOS; High-grade B-cell lymphoma with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma); High-grade B-cell lymphoma, NOS
• Availability of archival or freshly collected tumor tissue before study enrolment
• International Prognostic Index (IPI) score of 2-5
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
• Life expectancy greater than or equal to (>/=)12 months
• Left ventricular ejection fraction (LVEF) >/= 50 percent (%) on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
• Adequate hematologic function
• Female participants: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and refrain from donating eggs.
• Male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agreement to refrain from donating sperm.

Exclusion Criteria:

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines
• Prior organ transplantation
• Current Grade greater than (>) 1 peripheral neuropathy by clinical examination
• Demyelinating form of Charcot-Marie-Tooth disease
• History of indolent lymphoma
• History of follicular lymphoma grade 3B
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma)
• Primary mediastinal (thymic) large B-cell lymphoma
• Burkitt lymphoma
• Prior treatment with cytotoxic drugs within 5 years of screening for any condition (example [e.g.], cancer, rheumatoid arthritis) or prior use of any anti-CD20 antibody
• Prior use of any monoclonal antibody within 3 months of the start of Cycle 1
• Prior therapy for DLBCL, with the exception of nodal biopsy
• Corticosteroid use >30 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control
• Participants with central nervous system (CNS) lymphoma (primary or secondary involvement), primary effusion DLBCL, and primary cutaneous DLBCL
• Vaccination with live vaccines within 28 days prior to the start of Cycle 1
• Any investigational therapy within 28 days prior to the start of Cycle 1
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease
• Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis
• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significant infections within 2 weeks before the start of Cycle 1
• Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
• Prior radiotherapy to the mediastinal/pericardial region
• Participants with suspected active or latent tuberculosis
• Positive test results for chronic hepatitis B and hepatitis C infection
• Known history of human immunodeficiency virus (HIV) seropositive status
• Positive results for the human T-lymphotrophic 1 virus (HTLV-1)
• Participants with a history of progressive multifocal leukoencephalopathy

For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data\_sharing