From February through November of 1983, 199 cases of penicillin-resistant Neisseria gonorrhoeae infection were identified in a localized epidemic in Durham, North Carolina. The isolates did not produce beta-lactamase but were unusually resistant to penicillin (minimum inhibitory concentration, 2.0 to 4.0 micrograms per milliliter), and 15 of 16 patients treated with 4.8 million units of penicillin G procaine plus 1.0 g of probenecid did not respond to therapy. Recognition of the outbreak was impeded by a lack of routine surveillance for resistance other than that mediated by beta-lactamase. All epidemic isolates had a single serotype, auxotype, and antibiotic-susceptibility profile. The outbreak was halted by changing the treatment for all patients and their contacts to spectinomycin, and by intensive epidemiologic case-finding efforts. The emergence of such resistant strains poses potential major public health problems and indicates a need for reassessment of current surveillance procedures.