Cefotaxime (CTX) is considered one of the first-choice antibiotics in the therapy of spontaneous bacterial peritonitis (SBP) in cirrhosis. Because CTX is largely metabolized in the liver, this drug may also be effective in SBP by administering lower doses than those habitually used. To investigate this possibility, a prospective, randomized, multicenter study was performed to compare the therapeutic efficacy of two different dosages of CTX in 143 patients with SBP: 71 (group I) were allocated to receive a high dose (2 g every 6 hours, which is one of the most frequently recommended doses in this infection), and 72 (group II) were allocated to receive a low dose (2 g every 12 hours). At inclusion, both groups were similar in relation to clinical and laboratory data, with the exception of a higher incidence of positive ascitic fluid culture in group I than in group H (59% vs. 40%; P = .029). The rate of infection resolution was similar for both groups (77% vs. 79%). Hospital survival was also similar in both groups (69% vs. 79%). No difference was observed between patients with positive or negative ascitic fluid cultures with regard to infection resolution and patient survival. The duration of antibiotic therapy was similar in both groups (9.0 ± 3.3 days in group I vs. 8.8 ± 3.1 days in group II). In a subset of 13 patients from group I and 11 patients from group II CTX levels were determined in serum (peak and trough) and ascitic fluid (concomitantly with trough serum). Peak serum levels were similar in patients from both groups. In contrast, trough serum and/or ascitic fluid levels were significantly lower or more frequently undetectable in group II patients than in group I patients. Nevertheless, this feature did not correlate with infection resolution or patient survival. These results indicate that the High efficacy of CTX in SBP can be maintained by using doses lower than those habitually recommended.