ABSTRACT: Background: Coffee intake has been associated with risk of various cancers, but the findings, mostly from studies in white populations, are inconsistent. We examined the association of coffee consumption with overall cancer incidence and specific cancer sites in a large prospective study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites.Methods: 167,720 participants of the Multiethnic Cohort Study in Hawaii and Los Angeles were included. Baseline coffee intake was assessed by a validated food-frequency questionnaire. HRs and 95% confidence intervals (CIs) for sixteen cancers associated with coffee intake were calculated using Cox regressions.Results: During a mean follow-up of 15.3 years, 34,031 incident cancer cases were identified among study participants. Coffee intake was associated inversely with liver (?4 cups/day vs. none: HR = 0.57; 95% CI, 0.38-0.87; Ptrend < 0.001), ovarian (HR = 0.33; 95% CI, 0.17-0.65; Ptrend = 0.007), and thyroid (HR = 0.44; 95% CI, 0.23-0.87; Ptrend = 0.007) cancers and melanoma (HR = 0.72; 95% CI, 0.52-0.99; Ptrend = 0.002). Coffee intake was also inversely associated with endometrial cancer among women with a body mass index >30 kg/m2 (HR = 0.31; 95% CI, 0.14-0.72; Ptrend = 0.04). The associations were similar across five ethnic groups (Pheterogeneity > 0.06) and were mainly observed among those who drank caffeinated coffee.Conclusions: On the basis of our prospective data in diverse populations, we found a decreased risk of liver, ovarian, thyroid, and endometrial cancers and melanoma associated with higher coffee intake.Impact: These results suggest that coffee drinking may protect against liver, ovarian, thyroid, and endometrial cancers, and melanoma. Cancer Epidemiol Biomarkers Prev; 27(8); 928-35. ©2018 AACR.