The clinical benefit of highly active antiretroviral therapy (HAART) has been attributed to its suppression of viral replication and improvement in the CD4 lymphocyte count. However, the development of clinical symptoms secondary to previously silent opportunistic pathogens shortly after beginning HAART has been reported as a distinct clinical syndrome and seems to be associated with inflammatory phenomena surrounding a rapid restoration of the immune system in previously immunosuppressed patients. Herein, we report nine (3.6%) episodes of opportunistic infections (OI) in 247 human immunodeficiency virus (HIV)-infected patients undergoing HAART in a reference HIV/AIDS institution located in Madrid, Spain. In all instances, OI clustered within the first 3 months after beginning HAART. Episodes of cerebral toxoplasmosis (three cases), Pneumocystis carinii pneumonia (two cases), and herpes zoster (two cases) occurred in persons without a previous AIDS-defining illness, in addition a relapse of cytomegalovirus retinitis and a rebound in Kaposi's sarcoma were seen, respectively, in another two patients. Four of the nine subjects had a CD4 count above 200 cells/mm3 before HAART began. Of these, one developed Pneumocystis pneumonia and one other cerebral toxoplasmosis. In conclusion, prophylaxis and close clinical monitoring of HIV-infected patients should be considered for the first 3 months after beginning HAART, even for subjects without severe immunosuppression.