This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vemurafenib in participants with completely resected, cutaneous BRAF mutation-positive melanoma at high risk for recurrence. Participants will be enrolled in two separate cohorts: Cohort 1 will include participants with completely resected Stage IIC, IIIA (participants with one or more nodal metastasis greater than [>] 1 millimeter [mm] in diameter), or IIIB cutaneous melanoma, as defined by the American Joint Committee on Cancer (AJCC) Classification, Version 7; Cohort 2 will include participants with Stage IIIC cutaneous melanoma, as defined by this classification scheme. Within each cohort, participants will be randomized (1:1 ratio) to receive vemurafenib or matching placebo over a 52-week period.

Inclusion Criteria:

• Histologically confirmed melanoma of cutaneous origin
• Participants with BRAFV600 mutation-positive, cutaneous melanoma (either pathologic Stage IIC or Stage III according to AJCC Staging Criteria version 7 that has been completely resected
• BRAF V600 mutation status of the current primary tumor or involved lymph node determined to be positive using the cobas BRAF V600 mutation test
• Surgically rendered free of disease within 90 days of randomization
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 5 years
• Fully recovered from the effects of any major surgery or significant traumatic injury prior to the first dose of study treatment
• Adequate hematologic, hepatic, and renal function

Exclusion Criteria:

• History of any systemic or local therapy (e.g., chemotherapy, biologic or targeted therapy, hormonal therapy, or photodynamic therapy) for the treatment or prevention of melanoma, including interferon alpha-2b and pegylated interferon alpha-2b
• History of limb perfusion therapy
• History of radiotherapy for the treatment of melanoma
• Invasive malignancy other than melanoma at the time of enrollment or within 5 years prior to first dose of study treatment
• Family history of inherited colon cancer syndromes
• Known personal history of >3 adenomatous colorectal polyps or a personal history of adenomatous colorectal polyp(s) >2 centimeters (cm) in size
• History of or current clinical, radiographic, or pathologic evidence of in-transit metastases, satellite, or microsatellite lesions
• History of or current clinical, radiographic, or pathologic evidence of recurrent lymph node involvement after resection of a primary melanoma with lymph node involvement at any time in the past
• History of local and/or regional and/or distant melanoma recurrence
• History or current radiographic or pathologic evidence of distant metastases
• History of clinically significant cardiac or pulmonary dysfunction
• Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose of study treatment
• Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus