Hepatitis C virus (HCV) and hepatitis B virus (HBV) are etiological causes of hepatocellular carcinoma (HCC). Some studies suggest HIV co-infection increases HCC risk. From 1984-1992, 2206 distinct persons from New Jersey (NJ), 98% of whom had a history of injection drug use and/or were attending drug treatment programs (methadone maintenance, detoxification, or residential treatment), enrolled in three separate cohort studies utilizing similar protocols. Each study included extensive questionnaire data, HIV and HTLV testing, and banking of blood specimens with written consent permitting future testing and follow-up. Blood collected from 1989-1992 was later tested for HCV, demonstrating 99% were already exposed to HCV, so time of original HCV acquisitions is undeterminable. In a subset, HCV viral titers were measured; 80% had detectable titer. In a subset tested for HBV, only 2% had detectable HBV antigen. Of the 2206 persons: 60.7% male; 53.2% white, 34.3% Black, 11.9% Hispanic, 0.63% other/unknown; mean age 33.4 at enrollment (range 18.3-67.0). Overall, 29.5% were HIV seropositive with significant geographic variation. Cohort members' identifying information, including full and maiden names, alias(es), SSN, birthdate, sex, and race/ethnicity, was sent to the NJ State Cancer Registry (NJSCR) for linkage. Duplicate records using variations were created to maximize sensitivity. Using LinkPlus software, probabilistic matching of NJSCR records through 2012 was created. We reviewed purported matches using address information (available only on paper), National Death Index and Social Security Death Index matches, and previous matches to NJ State HIV and AIDS registries. Cancer outcome information was further supplemented with clinical information, medical records and pathology reports. There were 26 cases of HCC. Three occurred in HIV+ subjects (two initially HIV+, one who seroconverted ~7.5 months after study entry) with HCC diagnoses at 4.9, 10.9, and 27.7 years after study entry. No other HCC cases occurred among those of unknown HIV status or the other 88 documented HIV seroconverters. The other 23 HCC cases occurred in the 1434 HIV- subjects, diagnosed a mean 18.0 years (range 9.8-27.6) after study entry, a one-decade latency from enrollment until the first HCC case. Thereafter in the HIV-, HCC incidence increases linearly (linear regression fit r² = 0.98); annual rate is 0.83 HCC per thousand person-years. The lack of a plateau in cumulative incidence suggests that additional HCC cases will accrue. The general HCC epidemic in many geographic areas may thus be projected to continue. The advent of new HCV therapeutic agents will affect future risk of disease progression and sequelae. Timing of therapy may also affect the risk of progression to HCC. Relative risk ratios (RRR) and 95% confidence intervals for HCC among all 2206 persons were higher for males compared to females (RRR 1.21, CI 0.95-1.52); lower for Hispanics compared to non-Hispanic whites (RRR 0.73, CI 0.20-2.66); higher for Blacks compared to non-Hispanic whites (RRR 1.17, CI 0.76-1.81). The gender disparities between males and females are consistent with recent historical findings from Los Angeles 1993-1997 SEER data (male to female RRR=1.2 and 1.6 for whites and Blacks respectively) as well as racial disparities (Blacks to non-Hispanic whites RRR=1.3). However, our Hispanic to non-Hispanic white ratio differs from the Los Angeles and New Mexico 1993-1997 SEER data (RRR=2.4). The risk of HCC was significantly higher in the HIV- (p=0.03, 2-tailed) compared to those HIV+. This novel finding may in part reflect competing causes of death (with higher mortality rates in the HIV+, diminishing the HIV+ survivorship pool), our observed long latency from HCV acquisition to HCC (compounding the HIV+ higher mortality rates), and biologic factors. More comprehensive mortality data will permit life-table and covariate analyses. HCC has occurred in only 1.18% of this cohort. Although HCV was universal and persistent HBV infection was rare, the risks attributable to HCV and HBV (or their interaction) will require further laboratory work on the individuals. Testing of our banked specimens including those who developed HCC may better profile specific viral and other risk factors.