Background: Circadian misalignment may increase the risk of developing hepatocellular carcinoma (HCC). The aim of this study was to examine the association between distance from time zone meridian, a proxy for circadian misalignment, and HCC risk in the United States adjusting for known HCC risk factors. Methods: Surveillance, Epidemiology, and End Results (SEER) provided information on 56,347 HCC cases diagnosed between 2000 and 2014 from 16 population-based cancer registries in the United States. Distance from time zone meridian was estimated using the location of each SEER county's Center of Population in a geographic information system. Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between distance from time zone meridian and HCC risk adjusting for individual-level age at diagnosis, sex, race/ethnicity, year of diagnosis, SEER registry, and county-level prevalence of health conditions, lifestyle factors, shift work occupation, socioeconomic status, and demographic and environmental factors. Results: A 5-degree increase in longitude moving east to west within a time zone was associated with a statistically significant increased risk for HCC (IRR, 1.07; 95% CI, 1.01–1.14, P = 0.03). A statistically significant positive association was observed among those 〈65 years old, while no association was observed among individuals ≥65 years old ( P for interaction 〈 0.01). Conclusions: Circadian misalignment from residing in the western region of a time zone may impact hepatocarcinogenesis. Impact: Circadian misalignment may be an independent risk factor for HCC. Cancer Epidemiol Biomarkers Prev; 27(7); 719–27. ©2018 AACR .