17075 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Its incidence has doubled over the past 20 years in the United States. Determination of the pattern of occurrence of HCC as a second primary malignancy might give clues for new risk factors for HCC, or may reveal common genetic or environmental risks. Methods: We identified patients with a diagnosis of a second primary HCC between 1973 and 2002 using the Surveillance, Epidemiology, and End-Results Program (SEER) a compilation of population-based cancer registries in the United States, to calculate the observed to expected (O/E) frequency of second primary HCC after a different primary cancer. We stratified by ethnicity, latency from the year of diagnosis of primary cancer to HCC diagnosis, and period of diagnosis of primary cancer as early (1973–1987) or late (1987–2002). Results: We reviewed 1,931,911 subjects with cancer, and identified 1,185 second primary HCC cases. Overall, a second primary HCC after any primary cancer was less frequent than expected (O/E=0.82, 95% CI=0.77–0.87). We found positive associations with head and neck cancers (oral cavity/pharynx O/E=2.1, 95% CI=1.7–2.5), Kaposi's sarcoma (O/E=3.3, 95% CI=1.2–7.1) and Hodgkin's disease (O/E=2.3, 95% CI=1.2–4.0). Negative associations were seen for breast cancer (O/E=0.7, 95% CI=0.6–0.8), colorectal cancer (O/E=0.6, 95% CI=0.6–0.8), and prostate cancer (O/E=0.7, 95%CI=0.6–0.8). Overall, lower O/E ratios were seen in whites, while in African Americans and those of other races, the O/E ratios were close to one. Latency times were relatively short for head and neck cancers and Kaposi's sarcoma (most within 12–59 months), and greater than 120 months for most cases of HCC after Hodgkin's disease. All cases of Kaposi's sarcoma were seen in the later time period. Conclusions: These results highlight possible shared risk factors of alcohol ingestion and viral exposures which may predispose to second primary HCC after other primary malignancies. Providers should maintain heightened alertness for second primary HCC in these patients, especially those with head and neck cancers and HIV. No significant financial relationships to disclose.