There have been no population-based studies of the epidemiology and prognosis of patients with fibrolamellar carcinoma (FLC). We conducted a retrospective cohort study using information collected by population-based registries of the Surveillance, Epidemiology, and End Results (SEER) program. The demographic features, stage at diagnosis, and type of therapy, as well as age-adjusted incidence rates and observed and relative survival rates were compared between persons with FLC and those with hepatocellular carcinoma (HCC) diagnosed between 1986 and 1999. A multivariate Cox proportional hazards model was constructed to examine the effect of histology (FLC vs. HCC) on the risk of mortality. There were 68 microscopically confirmed cases of FLC and 7,896 cases of HCC. FLC constituted 0.85% of all cases of primary liver cancer and 13.4% of all cases below the age of 40. Compared to HCC, patients with FLC were more likely to be younger (mean age 39 vs. 65), female (51.5% vs. 26.3%), and white (85.3% vs. 56.9%). A greater proportion of case with FLC had localized disease (41.2% vs. 30.9%), or received potentially curative therapy (resection, transplantation), compared to cases with HCC. The age-adjusted incidence rate for FLC was 0.02 per 100,000; No significant differences in age-adjusted incidence rates were observed by gender or race. The 1- and 5-year observed and relative survival rates were significantly longer in patients with FLC than HCC. The 5-year relative survival rate was 31.8% (95% CI, 20.5%-43.1%) for FLC, compared with 6.8% (95% CI, 6.3 %-7.4 %) for HCC. Adjusting for differences in age, gender, race, stage of disease, receipt of resection or transplantation, and time of diagnosis, FLC was independently associated with a 46% reduction in risk of mortality within 5 years compared with HCC. In conclusion, in a population-based study, we observed remarkable differences in the epidemiology and prognosis of FLC compared to HCC.