Forty-one episodes of ascitic fluid infection were treated with cefotaxime 2 g intravenously every 8 hr, and ascitic fluid and serum were sampled 6, 12, 24, 48, and 96 hr after the first dose of antibiotic. Concentrations of cefotaxime and desacetyl cefotaxime were measured in ascitic fluid and serum by high-performance liquid chromatography. There was essentially 100% penetration of cefotaxime and metabolite from serum into ascitic fluid at all time points. Ascitic fluid was sterilized in 94% of episodes after the first dose of antibiotic. The ascitic fluid concentration of cefotaxime 6 hr after the first dose of antibiotic was greater than 20 times the minimal inhibitory concentration of the drug for 90% of the isolated flora. This rapid ascitic fluid penetration of cefotaxime in high concentration explains the rapid sterilization of ascitic fluid by the drug in the setting of bacterial peritonitis and obviates the need to give a loading dose or intraperitoneal injection.