Hepatocellular carcinoma (HCC) is one of the most common malignant primary liver tumors worldwide. A previous study showed a decline in pediatric HCC in Taiwan after the universal vaccination program was initiated in 1984. We investigated whether the recent change in HCC mortality in Taiwan represented a short-term fluctuation or an emerging long-term decline trend.An age-period-cohort analysis was conducted to show HCC mortality trends between 1976 and 2005. A total of 121,643 HCC mortality cases (92,926 males and 28,717 females) of individuals older than 40 years of age was used in the analyses.Results indicate an increasing secular trend in HCC mortality over the last three decades in people aged 60 years and above. In the age group of >85 years old, the mortality rate for males and females was 7.47 (95% confidence interval [95% CI]: 6.24–8.94) and 25.0 (95% CI: 15.5–40.2) times greater than in the youngest age group (40–44), respectively. The relative risk of dying from HCC in the period 2001–2005 was 1.36 (95% CI: 1.23–1.50) for males compared to the 1976–1980 time period, and 1.42 (95% CI: 1.17–1.72) for females compared to the 1986–1990 time period. A strong birth-cohort effect was also found. Individuals born around 1936 had the highest risk of dying from HCC.These findings imply that important determinants of HCC may occur early in life, with their effects only becoming apparent much later.