Diarrhea due to infection with Microsporidium (M) or Cryptosporidium (C) raises significant therapeutic challenges in HIV-infected patients. The usefulness of protease inhibitor therapy was evaluated in 20 HIV-positive patients with positive tests for M and/or C. There were 17 men and three women with a mean age of 42.5 years (range, 26-64 years). Two patients had category B disease and 18 category C disease according to the 1993 CDC classification scheme (CD4 count before therapy, 72/mm3; mean viral burden, 4.6 log). Seventeen patients had chronic diarrhea (due to M in 12 cases and to C in five), and the remaining three patients were asymptomatic M carriers. Clinical symptoms resolved after addition to the antiretroviral regimen of indinavir (n = 17) or saquinavir (n = 3). Mean weight gain was 10.5 kg. Karnofsky's index improved. Twelve patients, including one of the three who were asymptomatic at baseline, had negative follow-up stool cultures. The mean CD4 count increase was 125/mm3, and the mean viral burden decrease was 1.285 log. These data suggest that protease inhibitors may be capable of eradicating M and/or C infection refractory to other treatments. The reason for this effect may involve partial restoration of immune function due to inhibition of HIV replication.