Cefotaxime, a broad-spectrum third-generation cephalosporin, has been extensively used worldwide for chemotherapy of serious infections. Based on the characteristics of its antimicrobial spectrum, low incidence of allergy, and lack of adverse effects, cefotaxime has been used successfully for prophylaxis of a number of different surgical procedures. Extensive data have been accumulated for single-dose or short-course cefotaxime prophylaxis regimens. These cefotaxime regimens have been demonstrated to be very effective and inexpensive. For this article, over 11,500 published cefotaxime prophylaxis cases are reviewed (10,500 control cases) and 98 references are cited. Single-dose cefotaxime was clearly indicated for hysterectomies, cesarean sections, upper gastrointestinal cases, bone and joint operations, biliary tract procedures, transurethral resections, open urologic surgeries, and some vascular procedures. Short-course (3-4 doses) may be required for colorectal resections, cardiac surgeries, head and neck surgeries, organ transplants, specific pediatric surgical cases, and for some patients with compromised immune function, regardless of origin. Cefotaxime has reduced wound morbidity of contaminated abdominal operations to < 10%. This change from multiple-dose regimens to the single-dose or short-course regimens, enabled by cefotaxime use, decreases the risk of inducing or selecting bacterial resistance; the change would generate a significant reduction in hospital costs. Surgeons should not hesitate to employ cefotaxime and other third-generation cephalosporins with proven limited-dose indications to greatly benefit their patients and the hospital environment.