The photochemical fate of five sulfa drugs with varying five-membered heterocyclic substituents (sulfamethoxazole, sulfisoxazole, sulfamethizole, sulfathiazole, and sulfamoxole) was investigated in aqueous solution. The rate of direct photolysis of these compounds is dependent upon the identity of the heterocyclic R group as well as the pH of the solution. Matrix deconvolution methods were employed to determine the absorption spectrum and photolysis rate of each protonation state (cationic, neutral, and anionic). From these data, quantum yields for direct photodegradation were calculated for each protonation state of the sulfa drugs. The quantum yields calculated range from <0.005 for the neutral state of sulfamethizole to 0.7 ± 0.3 for the protonated state of sulfisoxazole. The protonation state that is most photoreactive varies among the sulfa drugs and cannot be attributed to the rate of photon absorption. Products arising from the direct photolysis of the sulfa drugs were also investigated. For all the compounds, sulfanilic acid was observed as a common product. The singlet oxygen quenching rates of the sulfa drugs were determined by laser flash photolysis and range from (2 ± 1) × 104 M-1 S-1 for sulfamethoxazole to (3.0 ± 0.7) × 108 M-1 s-1 for sulfamoxole. Reaction of the sulfa drugs with hydroxyl radical is not modulated by the R group, and the rate constants are all near the bimolecular diffusion-controlled limit of 10 10 M-1 s-1. The photodegradation of the sulfa drugs in natural water samples of Lake Josephine (St. Paul, MN) and Lake Superior was attributed solely to direct photolysis. This study indicates that these similarly structured antibiotics will be subject to a wide range of photodegradation rates with sulfathiazole degrading relatively quickly, sulfisoxazole and sulfamethizole degrading moderately, and sulfamethoxazole degrading much more slowly.