Background: Most US studies evaluating risk factors for HCC have used data from hospitals, cancer registries, or Veterans Affairs database. These data sources have small patient populations and limited generalizability. Methods: This study investigated the association between HCC and potential risk factors [hepatitis B and C virus (HBV, HCV), diabetes, alcoholism, cirrhosis, obesity, liver disease, dyslipidemia, hemochromatosis, and hypothyroidism] and compared to the general (non-HCC) population of ~60 million lives from an employer group database. A retrospective cohort analysis was conducted using the Marketscan Research Database from Thomason Reuters. Case patients had an ICD-9 diagnosis for HCC between 1/1/2001 – 12/31/2009 (index date) but no HCC diagnosis during 1-year prior to index date. Randomly selected control patients did not have HCC diagnosis, were matched 3:1 ratio and enrolled during same time period as matched case patients, and matched for age (+/- 1 year), gender, and geographical region. All patients were 18 - 65 years old and did not have any cancer diagnosis (except HCC for case patients). Data from 1-year prior to index date were used to identify risk factors. Demographic variables and prevalence of risk factors were analyzed using descriptive statistics. Multiple logistic regression was used to predict the odds of developing HCC compared to non-HCC patients for these risk factors. Results: The study included 1,208 case and 3,624 control patients. Mean age of cases and controls was 54 years and 67% were male. In unadjusted multiple logistic regression models, the risk for HCC was 48-fold and 135-fold increased for patients with HBV and HCV, respectively [95% confidence interval (CI): 6.2 – 374.4 for HBV, 31.5 – 580.8 for HCV]. Diabetes increased the risk for HCC by 3.85 (95% CI 2.5 – 5.9). Alcoholic cirrhosis and nonalcoholic (NA) fatty liver disease/NA steatohepatitis increased the risk for HCC by nearly 200-fold. Conclusions: Using a larger database, these study findings were consistent with previous research and provided further evidence that the risk of HCC is greatly increased in individuals diagnosed with hepatitis, diabetes, liver disease, and alcoholism.