PURPOSE: To compare the mortality and causes of death in human immunodeficiency syndrome (HIV) patients with the background population. METHODS: All adult HIV patients treated in Danish HIV centers from 1995 to 2008 and 14 controls for each HIV patient were included. Age-adjusted mortality rates (MR) and mortality rate ratios (MRR) were estimated using direct standardization and Poisson regression analyses. Up to four contributory causes of death for each person were included in analyses of cause-specific MR. RESULTS: A total of 5,137 HIV patients and 71,918 controls were followed for 37,838 and 671,339 person-years (PY), respectively. Among non-injection drug use (IDU) HIV patients, the acquired immune deficiency syndrome (AIDS)-related MR/1,000 PY declined dramatically from 122.9 [95 % confidence interval (CI) 106.8-141.4] in 1995 to 5.0 (95 % CI 3.1-8.1) in 2008. The non-AIDS-related MR did not change substantially from 6.9 (95 % CI 3.8-12.5) to 5.6 (95 % CI 3.6-8.8). The MR of unnatural causes declined from 6.9 (95 % CI 3.8-12.5) to 2.7 (95 % CI 1.4-5.1). The MRR of infections declined from 46.6 (95 % CI 19.6-110.9) to 3.3 (95 % CI 1.6-6.6). The MRR of other natural causes of death remained constant. CONCLUSIONS: After the introduction of highly active antiretroviral therapy (HAART), the AIDS-related mortality has decreased substantially, but the long-term exposure to HIV and HAART has not translated into increasing mortality from malignancy, cardiovascular, and hepatic diseases.