The effect of highly active antiretroviral therapy (HAART) on multiple acquired immunodeficiency syndrome (AIDS)-defining illnesses remains unclear. Between 1984 and 2005, 573 male human immunodeficiency virus seroconverters in four US urban centers were followed for a median of 9.7 years. During follow-up, 345, 113, 50, and 65 men incurred 0, 1, 2, and >2 AIDS-defining illnesses, respectively. The authors extend the Cox proportional hazards model to determine whether the effect of HAART, as measured by calendar periods, persists beyond the first AIDS-defining illness. After adjustment for race and age at seroconversion, the hazards of a first through third AIDS-defining illness in the HAART calendar period (beyond July 1995) were 0.31 (95% confidence interval (CI): 0.21, 0.46), 0.39 (95% CI: 0.22, 0.74), and 0.33 (95% CI: 0.14, 0.79), respectively, relative to the monotherapy and combination therapy reference calendar period (January 1990-July 1995) and therefore did not attenuate with the number of prior AIDS-defining illnesses (p for homogeneity = 0.83). After the authors averaged over multiple AIDS-defining illnesses, the hazard of an AIDS-defining illness in the HAART calendar period was 0.34 (95% CI: 0.25, 0.45) relative to the reference calendar period. HAART protects against initial and subsequent AIDS-defining illnesses, whose inclusion in analysis markedly increased the precision of the estimated hazard ratio.