BACKGROUND AND OBJECTIVES: Total knee arthroplasty (TKA) is associated with significant postoperative pain. Many intra-articular (IA) agents have been used for postoperative analgesia with inconsistent outcomes. Ketamine's enantiomer S(+), S(+)- ketamine, was recently introduced commercially, with higher analgesic potency and less side effects than the racemic form. An experimental prospective randomized double-blind study was conducted to evaluate the analgesic efficacy of intra-articular S(+)- ketamine in patients undergoing primary TKA. METHOD: In total, 56 patients were evaluated and allocated into three groups: Group A (n=19) received 0.25mg.kg(-1) of S(+)- ketamine diluted in 20mL of saline solution 0.9%; Group B (n=17) received 0.5mg.kg(-1) of S(+)- ketamine diluted in the same way; and Group C (n=20) received only 20mL of intra-articular saline 0.9%, immediately after surgery and drain placement. All patients had access to rescue analgesic therapy, with the use of intravenous morphine alone. Evaluations were made 2, 6, 12, and 24 hours postoperatively, with measurement of pain intensity by Visual Analogue Scale (VAS), use of rescue medication by the evaluation of the time elapsed between the intra-articular injection of the solution and first dose of rescue, total consumption within 24 hours, and adverse effects. RESULTS: The S(+)- ketamine groups had lower pain scores compared with the saline group. The lowest dose of intra-articular S(+)- ketamine (Group A: 0.25mg.kg(-1)) resulted in better pain scores and less rescue analgesia, with longer time to first request. Adverse effects were infrequent. The results with lower pain scores in groups using S(+)- ketamine are a trend, as there was no statistical significance between groups. CONCLUSION: In this study, with this sample, the analgesic effect of IA S(+)- ketamine was not superior to saline solution in the postoperative period of TKA.