Venlafaxine hydrochloride (Effexor) is a structurally novel antidepressant that inhibits reuptake of 5-hydroxytryptamine and noradrenaline, but unlike the older antidepressants, has few side-effects. The objective of this study was to determine whether venlafaxine relieves thermal hyperalgesia in rats with neuropathic pain due to chronic constriction injury (CCI) of the sciatic nerve. Paw withdrawal latency (PWL) to heat was tested for each hind paw. A painful neuropathy was induced in 24 male Sprague-Dawley rats (Group 1) as described by Bennett and Xie. Rats randomly received either oral venlafaxine (22 mg/kg) or placebo via gavage feeding beginning the day after surgery. Postoperative PWL testing began 3 days after CCI (Time 0). A second group of 12 rats (Group 2) was used to confirm that venlafaxine reverses hyperalgesia in rats with a fully developed neuropathic lesion. These animals began to receive oral venlafaxine (22 mg/kg) starting on the third postoperative day, after the presence of thermal hyperalgesia was verified through PWL testing. Testing was continued for 5 days, during venlafaxine administration. A third group of 12 rats (Group 3) had activity measured before and after treatment with venlafaxine (22 mg/kg). Rats in the placebo group developed thermal hyperalgesia while those that received venlafaxine did not. Venlafaxine also appeared to have a mild non-specific analgesic effect that increased PWL in the sham limb. In Group 2, thermal hyperalgesia was present on day 3, but following treatment with venlafaxine, thermal hyperalgesia resolved. Activity measurements confirmed that venlafaxine was not sedating in this rat model.