BACKGROUND Combinations of beta-lactams plus aminoglycosides have become standard therapy for suspected infections in patients with profound neutropenia. However, it is not clear whether such combinations are advantageous over therapy with a broad-spectrum antibiotic. OBJECTIVE To assess the clinical effectiveness and the cost-effectiveness ratio of empirical therapy of febrile neutropenia with imipenem/cilastatin (I/C) versus piperacillin/tazobactam plus amikacin (P/T+A). METHODS Prospective, multicenter observational study with 2 matched parallel cohorts treated with I/C (500 mg/6 h iv) or P/T+A (P/T: 4 g/6 h iv; A: 20 mg/kg/day iv). METHODS Therapeutic success was defined as the resolution of fever following > or = 7 days of unchanged antibiotic treatment. An economic comparison was conducted focusing on the daily treatment costs, and the management of its toxicity. RESULTS There were 343 eligible patients (180 I/C, 163 P/T+A), of whom 290 were evaluable for the primary clinical effectiveness analysis. Follow-up information beyond 7 days of study inclusion was only available for 52% of all evaluable patients. Treatment success was observed in 42% of I/C patients compared with 31% of P/T+A patients (95% CI: -0.01, 21.4). The incidence of drug-related adverse experiences was 13% for I/C and 6% for P/T+A, with no differences in moderate or severe adverse experiences nor in those causing discontinuation of antibiotic therapy. Treatment costs were 189.55 euros (95% CI: 127.46-251.46) lower per episode of febrile neutropenia for patients treated with I/C. CONCLUSIONS The clinical effectiveness of I/C was similar to that of P/T+A. In both treatment groups toxicity was low and did not limit antibiotic therapy. Resource consumption was lower with I/C.