Objectives: The mortality rate among AIDS cases reported through the notifiable disease system since its establishment in 1982 suggests higher excess mortality in Aquitaine compared to the rest of France. An analysis was conducted to determine whether AIDS mortality is higher among people with AIDS residing in Aquitaine and to identify the causes. Patients and methods: All AIDS cases reported between January 1, 1982, and June 30, 2005, were included. The relative risk of death among cases residing in Aquitaine was estimated using a Cox model adjusted for various subject characteristics, divided into two periods to account for the introduction of highly active antiretroviral therapy (HAART) in 1996. Results: Since 1982, 60,212 cases of AIDS have been reported. After adjusting for the subjects’ main characteristics, the risk of death was significantly higher in Aquitaine than in the rest of France (RR = 1.12, 95% CI = [1.06–1.18]) during the pre-HAART period. Since 1996, no significant difference has been observed (RR = 0.90, 95% CI = [0.75–1.09]). Conclusions: The higher case-fatality rate in Aquitaine compared to the rest of France was due to excess mortality in this region prior to 1996. Several hypotheses may explain this result, notably differences in the completeness of death reporting or regional variations in case characteristics. The situation appears to have reversed since 1996, but this trend will need to be monitored in the coming years.