OBJECTIVE Epidemiologic studies linking insulin glargine and glucose-lowering therapies to cancers and n-3 fatty acids to cancer prevention have not been confirmed. We aimed to assess the effect of insulin glargine and n-3 fatty acids on incident cancers within the context of the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial. RESEARCH DESIGN AND METHODS The ORIGIN trial is an international, long-term, randomized two-by-two factorial study comparing insulin glargine with standard care and n-3 fatty acids with placebo (double blind) in people with dysglycemia at high risk for cardiovascular events. The primary outcome measure (cancer substudy) was the occurrence of any new or recurrent adjudicated cancer. Cancer mortality and cancer subtypes were also analyzed. RESULTS Among 12,537 people (mean age 63.5 years, SD 7.8; 4,388 females), 953 developed a cancer event during the median follow-up of 6.2 years. In the glargine and standard care groups, the incidence of cancers was 1.32 and 1.32 per 100 person-years, respectively (P = 0.97), and in the n-3 fatty acid and placebo groups, it was 1.28 and 1.36 per 100 person-years, respectively (P = 0.39). No difference in the effect of either intervention was noted within predefined subgroups (P for all interactions ≥0.17). Cancer-related mortality and cancer-specific outcomes also did not differ between groups. Postrandomization HbA1c levels, glucose-lowering therapies (including metformin), and BMI did not affect cancer outcomes. CONCLUSIONS Insulin glargine and n-3 fatty acids have a neutral association with overall and cancer-specific outcomes, including cancer-specific mortality. Exposure to glucose-lowering therapies, including metformin, and HbA1c level during the study did not alter cancer risk.