Administration of targeted prophylaxis for AIDS-related opportunistic infections has contributed significantly to the recent decrease in mortality among patients with AIDS in the United States. Most reported prophylaxis trials have focused on determining (a) the percentage of cases prevented and (b) the effect of widespread antibiotic use on drug susceptibility. A third phenomenon that is seldom reported on is the attenuating effect of failed prophylaxis on the clinical presentation of opportunistic infections (OIs). With the increasingly widespread use of prophylaxis for OIs, more atypical "breakthrough" cases of opportunistic infections will be seen. Reports of clinical changes are reviewed below. Investigators should routinely report the clinical manifestations of breakthrough cases in all articles pertaining to prophylaxis for opportunistic infections in patients with AIDS.