A predictable 6- to 7-day course of a fatal Leptospira interrogans serovar bataviae infection in experimentally infected mature 110- to 150-g hamsters was used to evaluate the therapeutic efficacy of conventionally used and newer antibiotics. Active drugs were ampicillin, bacampicillin, cyclacillin, piperacillin, mezlocillin, doxycycline, chlortetracycline, cefotaxime, and moxalactam. Cephalexin, cefadroxil, cefamandole, and cefoperazone showed little or no activity in preliminary studies. In delayed treatment studies, all nine active drugs prevented death of hamsters even when treatment was delayed until 1 to 2.5 days before expected time of death. Leptospires in kidneys of surviving animals could be demonstrated in one or more hamsters treated with doxycycline, chlortetracycline, cyclacillin, and piperacillin, but in none of the animals treated with ampicillin, bacampicillin, mezlocillin, cefotaxime, and moxalactam. The potential usefulness of newer penicillins and cephalosporins, as well as ampicillin, chlortetracycline, and doxycycline, for treatment of severe leptospirosis is reported.