Cases of paradoxical worsening of opportunistic infections shortly after the beginning of highly active antiretroviral therapy (HAART) prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections. We describe three cases of acute respiratory failure after early introduction of HAART in patients treated for Pneumocystis carinii pneumonia (PCP). The three patients had severe PCP that initially improved with anti-PCP and adjunctive steroid therapy. HAART was introduced 1 to 16 d after diagnosis of PCP, and steroids were stopped on Day 15. Seven to 17 d after HAART introduction, the three patients developed a second episode of severe acute respiratory failure with high-grade fever and patchy alveolar opacities on the chest roentgenogram. PCP resistant to cotrimoxazole, pulmonary superinfection, and drug-related pneumonitis were suspected but subsequently ruled out. Bronchoalveolar lavage and lung pathologic findings showed severe nonspecific pulmonary inflammatory foci surrounding a few persistent P. carinii cysts. All three patients recovered after HAART interruption or steroid reintroduction. We conclude that acute respiratory failure can recur after initiation of antiretroviral therapy in patients being treated for severe PCP. This phenomenon could result from rapid pulmonary recruitment of fully competent immune and inflammatory cells responding to a few persistent P. carinii cysts. A short course of steroid therapy may suppress this reaction.