Background and AimsThe role of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) remains unclear. We investigated the associations of total fat and fatty acids with risk of HCC among US adults in a hospital‐based case–control study.MethodsWe analyzed data from 641 cases and 1034 controls recruited at MD Anderson Cancer Center during 2001–2018. Cases were new patients with a pathologically or radiologically confirmed diagnosis of HCC; controls were cancer‐free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck. Cases and controls were frequency‐matched by age and sex. Dietary intake was assessed using a validated food frequency questionnaire. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection.ResultsMonounsaturated fatty acid (MUFA) intake was inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.49; 95% CI, 0.33–0.72). Total polyunsaturated fatty acid (PUFA) intake was directly associated with HCC risk (highest vs. lowest tertile: OR, 1.82; 95% CI, 1.23–2.70). Omega‐6 PUFA was directly associated with HCC risk (highest vs. lowest tertile: OR 2.29; 95% CI, 1.52–3.44). Long‐chain omega‐3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) intake was also inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.50; 95% CI, 0.33–0.70). No association was observed for saturated fat and HCC risk.ConclusionOur findings support a direct association of omega‐6 PUFA intake with HCC and an inverse association of MUFA and long‐chain omega‐3 PUFA intake with HCC.