Background: Hepatocellular carcinoma (HCC) is a malignant cancer of the liver and a leading cause of cancer-related mortality worldwide. Human immunodeficiency virus (HIV) has not been known to have a direct causal relationship with HCC despite independently causing inflammation of the liver. However, little is known on risk factors for HCC patients in an HIV endemic area. The objective of this study was to ascertain the risk factors of HCC and its association with HIV infection. Methods: This was an un-matched case-control study conducted between June 2015 and June 2016 in Kisumu County Referral Hospital, Kenya. The study enrolled 257 patients with HCC cases and 257 controls. A multivariable logistic regression analysis was used to assess the risk factors for HIV and controlling for exploratory variables. Independent t-test was used to compare means. Exposure variable with values < 0.05 were considered to be statistically significant. Results: HCC cases were more likely to be above 35 years old compared to controls (88.3% vs 23.0%), [aOR =51.6,95% CI (27.8–95.6), P< 0.001)]. HBV infected patients have higher risk of HCC (47.1% vs 30.4%), [aOR = 3.3; 95% CI (1.7–5.0), P< 0.0001)]. HIV positive patients were more likely to have HCC than HIV negative patients (33.5% vs 10.9%), [aOR =4.3, 95% CI (2.2–8.4)), P< 0.001]. Females have lower risk of HCC than males (32.7 vs 23.7) [a OR = 0.2, 95% CI (0.1–0.4), P < 0.001]. The majority of HCC patients were at the time of diagnosis at stages C (35.1%) and D (48.6%)according to the Barcelona Clinic Liver Clinic (BCLC) criteria. Conclusion: Liver cancer was more frequent among adults and subjects co-infected with HBV and HIV. Thus, HIV represents an additional risk factor for liver cancer in this Kenyan population. Regular health screening of HIV and HBV infected subjects may significantly improve the early diagnosis and effective therapy of liver cancer