Sulfamethoxazole and trimethoprim are synergistic against many bacteria in sulfamethoxazole/trimethoprim concentrations of 20:1, but single-dose therapy of gonorrhea with the combination is disappointing. We used agar dilution techniques to determine minimal inhibitory concentrations of sulfamethoxazole and trimethoprim for 168 gonococci isolated from men with acute urethritis in Atlanta, Ga. The geometric mean minimal inhibitory concentrations were 5.6 microgram of sulfamethoxazole per ml and 24.3 microgram of trimethoprim per ml, a ratio of 1:4. The concentration of sulfamethoxazole inhibiting 50% of gonococcal strains dropped only from 4.7 microgram/ml to 2.9 microgram/ml with the addition of a 1/20 dilution of trimethoprim. We studied synergism with various ratios of sulfamethoxazole to trimethoprim against 20 random strains. A ratio of 1:1 was always synergistic and was the most synergistic ratio for 15 strains, whereas the 19:1 ratio was never the most syngergistic. The 19:1 ratio failed to show synergism against seven strains, but showed antagonism at this ratio with five of these seven. The sulfamethoxazole/trimethoprim ratio of 19:1 usually achieved in serum after oral administration is minimally syngergistic and is sometimes antagonistic for gonococci.