Background: Oral antifungal therapies are effective for onychomycosis but it was complicated by systemic effects. Effective and safe therapy is needed to improve esthetic appearance of nails. Objective: The present study is an attempt to evaluate and compare the efficacy of of combined treatment of onychomycosis with 1,064-nm long-pulsed Nd-Yag laser and pulse itraconazole therapy versus pulse itraconazole alone. Methods: Thirty onychomycosis patients were divided into two groups: Groups I and II. Patients of Group I are treated by itraconazole pulse therapy. Patients of Group II received six laser sessions with longpulsed Nd:Yag laser and itraconazole pulse therapy. The investigators rated clearance using “Onychomycosis Severity Index (OSI)”, photographs, and mycology at 6 and 9months after treatment. Results: Group I’s clinical improvement response was excellent in two cases, good in six cases, moderate in five cases, and mild in two cases. Mycological improvement response was excellent in two cases, good in two cases, moderate in six cases, and mild in five cases (OSI before treatment was 13.4 ± 3.02 and after was 6.67 ± 3.6). Group II’s clinical improvement response was excellent in 10, good in 3, moderate in 1, and mild in 1. Mycological improvement’s response was excellent in two cases, good in two cases, moderate in six cases, and mild in five cases (OSI before treatment was 13.33 ± 3.11 and after was 5.07 ± 4.15). There were no adverse effects. The clinical response showed best results with Group II, but the mycological cure was equal in both groups. Conclusions: The use of combined long-pulsed Nd-Yag laser and itraconazole pulse therapy gives the best clinical results and patient’s satisfaction.