BACKGROUND: Low diet quality, diabetes, and chronic inflammation are risk factors of liver cancer and chronic liver disease (CLD), but the extent to which insulinemic and inflammatory diets are independently associated with risk of liver cancer and CLD mortality is unknown. METHODS: We conducted a prospective cohort analysis among 78,356 postmenopausal women in the Womens Health Initiative Observational Study. Two validated dietary indices, the empirical dietary index for hyperinsulinemia (EDIH) and the empirical dietary inflammation pattern (EDIP), were estimated from a food-frequency questionnaire. Incident cases of liver cancer and CLD mortality were adjudicated via review of medical records and linkage to National Death Index. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models, adjusted for age, diabetes, body mass index, and other covariates. RESULTS: During a median 22.1 y of follow-up, we documented 176 primary liver cancer cases and 156 CLD mortality cases. EDIH was positively associated with incident liver cancer (HRQuartile 4 vs. Quartile 1 = 1.68; 95% CI: 1.00, 2.83; P-trend = 0.05) and CLD mortality (HRQ4 vs. Q1 = 2.28; 95% CI: 1.25, 4.15; P-trend = 0.02) in the multivariable model. EDIP was also positively associated with liver cancer (HRQ4 vs. Q1 = 1.88; 95% CI: 1.17, 3.03; P-trend = 0.009) and CLD mortality (HRQ4 vs. Q1 = 1.85; 95% CI: 1.09, 3.15; P-trend = 0.007). Estimates remained significant and robust in sensitivity analyses. Further analyses indicated positive associations for refined grains, processed meat, sugary beverages, and eggs, and inverse associations for coffee/tea and poultry. CONCLUSIONS: Dietary insulinemic and inflammatory potentials were independently associated with higher risk of liver cancer and CLD mortality in U.S. postmenopausal women. These findings suggest a potential role for diet modification to reduce risk of liver cancer and CLD.