The objective of this study was to determine the risk factors of the first occurrence of Mycobacterium avium complex disease (MAC) infection among human immunodeficiency virus (HIV)-infected subjects during two different time periods: before and after the introduction of protease inhibitor (respectively, period 1: 1 January 1992 to 31 December 1995, and period 2: 1 January 1996 to 30 June 1998). This study was performed using the French Hospital Database on HIV (FHDH). Subjects were included when their CD4+ cell count was less than 100/mm3. If they did not die or develop MAC within the first 6 months after the inclusion, their follow-up had to be longer than 6 months to be included. Cox's model was used to calculated the relative hazards (RH) of MAC occurrence according to the age and time-dependent variables, such as CD4+ below 50/mm3, previous occurrence of tuberculosis, cytomegalovirus (CMV) infection and other acquired immunodeficiency syndrome (AIDS)-defining disease, nature of antiretroviral treatment and MAC prophylaxis. Among the 14,779 subjects followed during period 1, 1,710 (11.6%) had a diagnosis of MAC infection during their follow-up (incidence: 8.4 +/- 0.2 for 100 persons per year), while only 453 (4.4%) among 10,239 subjects presented this infection during period 2 (2.8 +/- 0.1 for 100 persons per year). Rifabutin regular prescription was a protective factor of MAC occurrence during period 1 (RH = 0.51 95% confidence interval (CI) = [0.37-0.69]), whereas this protective effect was not observed during period 2 (RH = 1.05 CI = [0.63-1.67]). Thus, during the HAART period, the results that we present do not indicate an interest into continuing MAC prophylaxis.