A chart review of 73 human immunodeficiency virus (HIV)-infected patients with enteric microsporidiosis was conducted to define the natural history of microsporidiosis. A substantial proportion of patients remained symptomatic after 6 months (54.8% with persistent diarrhea and 51.2% with weight loss). Predictors for persistent diarrhea included high HIV RNA viral load and no initiation of protease inhibitor therapy.