Post-appendicectomy sepsis still causes considerable morbidity and prolongs hospital stay. A large amount of recent work has gone into attempts to reduce such problems using various topical and systemic agents in differing regimes, with wide variation in their results. The aim of our study was to examine further the effectiveness of those different lines of prophylaxis against placebo in reducing post-appendicectomy sepsis. It is a comparative study of 400 cases of uncomplicated appendicitis operated upon by three senior Surgeons. The cases were allocated randomly in equal number to four groups according to the prophylactic antibiotic regime used: (a) Placebo; (b) Metronidazole alone; (c) Metronidazole and cefazolin; (d) Metronidazole and tobramycin. Antibiotics were given preoperatively with premedication and continued postoperatively for three days. The patients were checked for signs of sepsis during hospital stay and weekly up to a minimum of four weeks after discharge. They were also compared as far as their hospital stay is concerned. The conclusion of this study is that a combination of an antibiotic aimed at aerobes (cefazolin or tobramycin) with another aiming at anaerobes (metronidazole) is the best prophylactic regime against post-appendicectomy sepsis.