We report three patients (followed up for 13, 9, and 12 years) who had multiple episodes of disseminated histoplasmosis. Clinically, all three patients had high yields of positive cultures and all developed corticoadrenal insufficiency; all survived the recurrent relapses. One patient had unilateral progressive panophthalmitis, with ocular cultures positive for Histoplasma capsulatum. These relapses occurred despite conventional treatment with large doses of amphotericin B. Prolonged remissions were associated with using small doses of this drug. One patient had a long-term remission while taking ketoconazole daily for more than four years. These patients did not have conditions associated with immunosuppression. Lymphocyte proliferation to mitogens and, in one patient, to histoplasmin, was markedly reduced at the time of relapse and when tested preceding a relapse. All three patients showed a reversal to normal lymphocyte proliferation at the time of the longest last remission.