Objectives: The aim of this study was to investigate effect of zimelidine (a serotonin reuptake inhibitor) on morphine-induced tolerance in rats. Materials and Methods: Male Wistar albino rats weighing 160-180 g were used in these experiments (n=72). A 3-day cumulative dosing regimen was used for the induction of morphine tolerance. To constitute of morphine tolerance, animals received morphine twice daily for 3 days. After the last dose morphine was injected on the fourth day, morphine tolerance was evaluated. The analgesic effects of zimelidine (15 mg/kg; i.p.) and morphine (5 mg/kg) were considered at 30-min time intervals (0, 30, 60, 90 and 120 min) by tail-flick and hot-plate analgesiometer (n=6 in each experimental group). Results: The results showed that zimelidine significantly attenuated the development and expression of morphine tolerance. The maximal antinociceptive effect of zimelidine was obtained at the 60 minutes measurements in the zimelidine group and at the 30 minutes measurements in the morphine tolerant group by the tail-flick and hot-plate tests. Administration of zimelidine with morphine showed additive analgesic effect. Conclusion: In conclusion, our results show that zimelidine reduces the development of tolerance to morphine-induced antinociception in rats.