Patient collaboration in external shock wave lithotripsy (ESWL) is critical for its correct application, making proper analgesic selection indispensable. The aim of this study was to evaluate the efficacy of combined application of EMLA and intravenous (i.v.) pethidine compared with pethidine plus placebo cream in patients undergoing ESWL for ureteral and/or renal lithiasis. Prospective, controlled, randomized, double-blind study was conducted in patients receiving ESWL for renal and/or ureterolithiasis. The patients were randomly assigned to receive i.v. pethidine plus either EMLA cream (group A) or placebo hydrating cream (group B). Evaluated were type, location, and size of lithiasis, patient's sex, age, body mass index, comorbidity, Visual Analogue Scale (VAS) score of pain, and degree of lithiasis fragmentation. EMLA cream provided significantly better pain relief and lithiasis fragmentation and more completed ESWL treatment. Topical application of EMLA cream combined with i.v. pethidine improved VAS scores and lithiasis fragmentation and decreased the rate of withdrawal from ESWL procedure versus i.v. pethidine plus placebo therapy.