571 Background: The effect of lifestyle factors, namely alcohol use, cigarette smoking, and other forms of tobacco use on hepatocellular carcinoma (HCC) remains unclear. We assessed the independent associations of lifestyle factors with HCC among individuals with and without viral hepatitis. Methods: In a hospital-based case-control study recruiting from Mulago and Lacor hospitals in Uganda from March 2015 to August 2021, HCC cases were confirmed by clinical and ultrasound criteria, with biochemical and pathology confirmation on a subset. Controls were frequency matched by age and sex and from the same hospitals. Demographic, clinical and lifestyle data were collected using standardized instruments. Alcohol content of local drinks was standardized, and intensity categorized as light, moderate, or heavy based on CDC definitions. We analyzed alcohol (use status (current, former, never), duration (years), frequency (drinks/week)), cigarette smoking (status (current, former, never), cumulative (pack‐years), duration (years), intensity (cigarettes/day), and time since cessation), other tobacco use (tobacco chewing and pipe-smoking), and viral hepatitis (HBV surface antigen (HBsAg) and HCV antibody (HCVAb)). We used logistic regression models (Stata 18.0) to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CIs) controlling for age, sex, family history of HCC, socioeconomic status, and Schistosomiasis (urine Circulating Cathodic Antigen (CCA)). Stratified analyses were performed separately by HBV and HCV status. Results: Among 596 HCC cases and 1,277 controls, the median age (IQR) was 43 (32-56) and 45 (31-54) years, 410 (68.8%) and 832 (65.0%) were males, 460 (24.6%) and 442 (23.7%) current or former alcohol users, 96 (5.1%) and 251 (13.4%) current or former cigarette smokers, and 177 (9.45%) and other tobacco users, respectively. Other tobacco users were more likely to be heavy (⩾10 pack-years) cigarette smokers (aOR=5.10; 95% CI: 2.41-10.79), heavy (>14 drinks/week for males and >7 drinks/week for females) alcohol drinkers (aOR=5.25; 95% CI: 2.84-9.68), farmers (aOR=1.61; 95% CI: 1.01-2.57) and lower socioeconomic status (aOR=3.23; 95% CI: 1.76-5.94). HCC risk was associated with HBV (aOR=18.66; 95% CI: 12.96-27.88), HCV (aOR= 4.03; 95% CI:2.31-7.02), and other tobacco use (aOR=1.86; 95%CI: 1.13-3.08). The observed HCC risk with other tobacco use, and the null associations with heavy alcohol use (aOR= 0.89; 95% CI: 0.60-1.31) and heavy cigarette smoking (aOR=0.74, 95% CI:0.34-1.60), were homogenous by HCV status (positive versus negative), and similarly by HBV status. Conclusions: Viral hepatitis (HBV and HCV), and lifestyle factors (tobacco chewing and pipe-smoking) were strongly associated with HCC. Further research should explore the role of tobacco chewing and pipe-smoking in HCC risk in Uganda and similar settings in Sub-Saharan Africa.