We evaluated the efficacy and safety of ceftriaxone in 50 adults with serious infections, usually giving 1 g every 12 h. Of the 35 patients who could be evaluated for clinical efficacy, 15 had failed on previous therapy, 15 had nosocomial infections, and all but 1 had underlying diseases. One patient had three sites of infection. Favorable responses were seen in 34 of 37 infections, including 11 of 13 respiratory tract infections, all 7 urinary tract infections, all 12 skin and soft tissue infections, 1 of 2 bone and joint infections, a catheter-related septicemia, a liver abscess, and an otitis media and externa. Favorable bacteriological responses were seen for 48 of 58 organisms. This included 6 of 7 Staphylococcus aureus strains, 14 of 16 other aerobic gram-positive cocci, 18 of 20 Enterobacteriaceae, 6 of 9 Pseudomonas aeruginosa, and 1 of 2 anaerobes. Peak plasma ceftriaxone levels on day 1 were 152 μg/ml by bioassay and 78 μg/ml by high-pressure liquid chromatography. Four of the 31 initial isolates of aerobic gram-negative rods developed resistance to ceftriaxone on disk diffusion testing. Diarrhea occurred in 3 of 50 patients. All three had received a higher than usual dose. Drug administration was stopped twice, once for a thrombocytopenia and once for a thrombocytopenia with leukopenia. Neither problem could be attributed exclusively to ceftriaxone. Other adverse reactions were eosinophilia, abdominal pain, inguinal candidiasis, and nonsuppurative phlebitis. Even among debilitated adults, ceftriaxone was safe and effective in a twice daily regimen.