This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vismodegib plus (+) ruxolitinib versus placebo + ruxolitinib in participants with intermediate- or high-risk MF. The study will be divided into 2 components. The Phase Ib portion of the study consists of participants receiving open-label vismodegib (150 milligrams [mg] orally [PO] once daily [QD]) + ruxolitinib (PO twice daily [BID]). A safety assessment will be performed after the first 10 participants have been treated for 6 weeks. An analysis for efficacy and safety is planned in the first 10 participants at Week 24. There will be a hold on participant screening and enrollment during this assessment. Another 10 participants may be enrolled, thereafter, to further assess efficacy and safety (at Week 24) before the initiation of the Phase III randomization portion of the study. Similarly, there will be another hold on participant screening and enrollment during this assessment. The participants enrolled in the Phase Ib portion of the study will continue to receive vismodegib (150 mg PO QD) + ruxolitinib (PO BID) for up to 48 weeks, if clinical benefit is observed after 24 weeks. The Phase III randomized, double-blind portion of the study will enroll approximately 84 participants. Participants will be randomly assigned in a 1:1 ratio (double blind) to receive either vismodegib (150 mg PO QD) + ruxolitinib (PO BID) or placebo (PO QD) + ruxolitinib (PO BID) for up to 48 weeks.

Inclusion Criteria:

• Pathologically confirmed diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, according to the 2008 revised World Health Organization criteria
• Intermediate-1, intermediate-2, or high-risk according to the IWG-MRT Dynamic International Prognostic Scoring System
• Life expectancy >= 6 months
• Peripheral blood blast count of less than (<) 10%
• Palpable splenomegaly of greater than (>) 5 centimeters (cm) below the left costal margin
• Eastern Cooperative Oncology Group performance status of 0 to 2
• Adequate hepatic and renal function

Exclusion Criteria:

• Prior treatment with a Hedgehog or Janus kinase pathway inhibitor
• Treatment with strong cytochrome P450 3A4 inhibitors/inducers within 28 days prior to Day 1
• Prior therapy for the treatment of intermediate- or high-risk MF including chemotherapy, interferon, thalidomide, busulfan, lenalidomide, anagrelide, or androgens within 28 days prior to Day 1
• Prior splenectomy or splenic irradiation
• Inadequate bone marrow reserve
• Participants with any history of platelet counts of < 50,000/mccL or ANC of < 500/mL, except during treatment for myeloproliferative neoplasm or treatment with cytotoxic therapy for any other reason
• Planned allogeneic bone marrow transplant during the study