Epidural analgesia remains the "gold standard" of pain relief after total knee replacement. However, peripheral nerve block is gaining popularity because the incidence of side effects may be reduced. Our study tests this postulate. Sixty patients were prospectively randomized to receive either epidural infusion or combined continuous femoral and sciatic nerve blocks. Ropivacaine 2 mg/mL plus sufentanil 1 mug/mL was given either epidurally or through the femoral nerve catheter, and ropivacaine 0.5 mg/mL was given through the sciatic nerve catheter using elastomeric infusers (delivering 5 mL/h for 55 h). The primary outcome measure was the total incidence of side effects (urinary retention and moderate to severe degrees of dizziness, pruritus, sedation, and nausea/vomiting on the first postoperative day). Intensity of motor blockade, pain at rest and on mobilization, and rehabilitation indices were also registered for 72 h. One or more side effects were present in 87% of patients in the epidural group whereas only 35% of patients in the femoral and sciatic block groups were affected on the first postoperative day (P = 0.0002). Motor blockade was more intense in the operated limb on the day of surgery and the first postoperative day in the peripheral nerve block group (P = 0.001), whereas the non-operated limb was more blocked in the epidural group on the day of surgery (P = 0.0003). Pain on mobilization was well controlled in both groups and there were no differences in the length of hospital stay. Rehabilitation indices were similar. The results demonstrate a reduced incidence of side effects in the femoral/sciatic nerve block group than in the epidural group on the first postoperative day.