An effective empirical treatment regimen would provide a more rapid and less expensive approach to the management of homosexual men with acute proctitis. We conducted a randomized trial in 129 homosexual men who presented with acute proctitis, comparing treatment with an empirical regimen (4.8 million U of aqueous penicillin G procaine intramuscularly and 1.0 g of probenecid orally, followed by 100 mg of oral doxycycline twice daily for seven days) with specific therapy for each infection as it was recognized. Therapy with the empirical regimen resulted in more rapid resolution of the symptoms of proctitis, the objective signs of proctitis, and the infecting microorganisms. However, nearly one fourth of the patients, primarily those with unrecognized herpes simplex virus proctitis, did not respond to empirical therapy. We recommend empirical therapy coupled with appropriate pretreatment diagnostic testing for the initial management of acute proctitis in homosexual men with no clinical evidence of acquired immunodeficiency syndrome or AIDS-related complex.