Baclofen is an agonist for a subtype of gamma-amino butyric acid (GABA-B) receptors and traditionally been used for the systemic treatment of spasticity. Topical application of baclofen has been shown to reduce pain in patients with localized neuropathic pain. In this study, we investigate the efficacy of baclofen cream (5%) in reducing postoperative pain and analgesic requirement after open hemorrhoidectomy. The patients were randomly assigned to either baclofen (5%) cream or placebo immediately after surgery and then every 12 h for 14 days. A total of 66 patients with third- and fourth-degree hemorrhoids undergoing open hemorrhoidectomy were randomly assigned to this trial. This study was conducted at a single educational hospital. The primary outcomes were intensity of pain, measured with a visual analog scale, and the analgesic requirement, measured by the amount of the acetaminophen consumption. No significant difference was found in baseline characteristics between the two groups. Postoperative pain score of the baclofen group was significantly lower on week 1 (P = 0.01) and week 2 (P = 0.02) than the placebo group. Similarly, patients in the baclofen group consumed significantly less analgesic medication on week 1 (P = 0.025) and week 2 (P = 0.024) than the control group. Topical application of baclofen effectively relieves pain after hemorrhoidectomy with minimal side effects.