Summary Several studies have investigated the presence of a drug interaction between tramadol and ondansetron that reduced the efficacy of tramadol postoperatively. Most of these studies were small and the results inconsistent, so we performed a systematic review and meta-Analysis of randomised controlled trials comparing the cumulative dose of tramadol administered by patient-controlled analgesia within the first 24 h after surgery between subjects receiving tramadol alone and those who received tramadol with ondansetron. Six studies, with a total of 340 participants, met the selection criteria and were included in the meta-Analysis. There was an increased tramadol requirement in patients receiving ondansetron. The standardised mean difference in tramadol requirements, expressed in terms of standard deviations (95% CI), was 1.03 (0.54-1.53) (p < 0.001) at 4 h, 0.66 (0.06-1.25) (p = 0.03) at 8 h, 0.86 (0.41-1.31) (p < 0.001) at 12 h and 0.45 (0.01-0.90) (p = 0.046) at 24 h postoperatively, where the mean pooled standard deviations were 79.5, 157.7, 238.1 and 289.4 mg at 4, 8, 12 and 24 h, respectively. There was a significant linear time effect over the 24 h, indicating that the effect of ondansetron on tramadol consumption diminished with time. The results support the presence of a drug interaction between tramadol and ondansetron in the early postoperative period that potentially decreases the effectiveness of tramadol.