The objective of the investigation was to determine the comparative efficacy of cefotaxime versus trimethoprim-sulfamethoxazole in the prophylaxis of patients undergoing neurosurgical procedures. In this prospective randomized open study, 780 adult patients undergoing elective craniotomy, shunt surgery or stereotactic surgery were randomized to receive preoperative cefotaxime (1 g) or trimethoprim-sulfamethoxazole (160 mg trimethoprim, 800 mg sulfamethoxazole) as prophylaxis: 613 patients were available for analysis, of whom 315 received cefotaxime and 298 received trimethoprim-sulfamethoxazole. Forty-two patients (6.9%) experienced 49 postoperative infections, with no significant difference between treatment groups. The most common infections unrelated to neurosurgery were urinary tract infections (17 cases) and pneumonia (seven cases). Fifteen neurosurgical infections occurred, comprising 11 wound infections, two shunt infections and two cerebral abscesses. Neurosurgical infection rates were similar in the cefotaxime group (2.5%) and the trimethoprim-sulfamethoxazole group (2.3%). We concluded cefotaxime and trimethoprim-sulfamethoxazole administered as single dose prior to neurosurgery are equally effective in controlling neurosurgical infection and postoperative infection at remote sites.