The most common complications after surgical extraction of the third mandibular molar are trismus, oedema or swelling, local pain, dysphagia and infection. The aim of this comparative, double-blind, randomized clinical trial was to evaluate the efficacy of two sustained release amoxicillin/clavulanate regimens in the reduction of infection after third molar extractive surgery. A total of 225 patients were randomized into three equal groups: placebo, prophylaxis with single pre-surgical dose of two tablets amoxicillin/clavulanate 1000/62.5 mg, and pre-emptive post-surgery therapy with two tablets amoxicillin/clavulanate 1000/62.5 mg BID for 5 days. A higher rate of infection (P=0.006) was found among patients receiving placebo (16%) than those receiving single-dose prophylaxis (5.3%) or 5-day pre-emptive therapy (2.7%). A relationship between both the duration (13.8% for long versus 7.4% for medium versus 1.6% for short) and difficulty (12.7% with ostectomy versus 3.5% without ostectomy; P=0.011) of surgical procedure and incidence of subsequent infection was also observed. Both prophylactic and therapeutic regimens versus placebo achieved greater reduction of pain after surgery on day 3 (P=0.001). Logistic regression analysis revealed a risk of infection of 24%, 9% and 4% for ostectomy with placebo, prophylaxis and pre-emptive treatment, respectively, whereas it was 7%, 2% and 1% if ostectomy was not performed. Pre-emptive therapy with the oral sustained release amoxicillin/clavulanate formulation reduced the rate of subsequent infection in patients undergoing ostectomy. Prophylaxis was beneficial in simpler procedures and may be indicated in cases where ostectomy is not performed.