Background: Nevus spilus can produce considerable disfigurement. There is no specific and successful treatment for this nevus. Objective: The purpose of this study was to evaluate the efficacy of CO2 laser in the treatment of nevus spilus. Patients and Methods: This quasi-experimental clinical trial was performed on 47 patients with spilus nevus in Al-Zahra Hospital in Isfahan. The diagnosis of nevus spilus was based an clinical and biopsy findings. The efficacy of treatment was evaluated based on tolerability, side effects, improvement according to patient and physician judgment and comparison of photographies, after one year of follow up. The laser used was Sonic LS 500 (Made in Germany) with power of 3 watts, duration of 0.25 seconds and spot size of 3 millimeters. Results: 45 of the patients were female and 2 were male. The mean age of them was 20 years. All the lesions were on the face. Two patients were withdrawn due to inefficacy or infection of test site treatment. In 43 of the 45 remaining patients (95.5%), the treated site healed uneventfully. Recurrence of nevus spilus was seen in a single patient one year after treatment. Conclusion: CO2 laser is an effective therapy for nevus spilus.