Two of the 3rd generation cephalosporins, ceftriaxone and cefotaxime, have an almost identical antibacterial spectrum, but completely different pharmacokinetics. After an intravenous dose of 1 g, peak levels of both cephalosporins were > 100 μg/ml. Cefotaxime levels fall rapidly with a T½ of 1.1 h, whereas ceftriaxone persists for 24 h with an unique T½ of 8 h. Cefotaxime is eliminated by the kidneys and metabolized to desacetyl-cefotaxime resulting in a high total clearance. In contrast, ceftriaxone is not metabolized and highly protein bound with a total clearance of only 14 ml/min. Peak concentrations of antibiotics are lower in extravascular compartments than in serum. They depend on the dose administered and the serum T½; they are lower with highly bound drugs. Concentrations of ceftriaxone and cefotaxime were measured by Andrews and Wise in blister fluids, in ascites and pleural fluid by us. We found concentrations of 20–26 μg/ml ceftriaxone up to 12 h in ascites, but only 7–15 μg/ml cefotaxime. The levels persisted for 24 h for ceftriaxone, whereas they fell rapidly for cefotaxime. Because the minimum inhibition concentrations increase in the presence of proteins, and because free, unbound, microbiologically active ceftriaxone is lower than the measured total antibiotic concentrations, we suggest that 2-gram doses should be administered – at least at the beginning of the treatment of an infectious disease – and for prophylaxis.