BACKGROUND: Onychomycosis is a therapeutic challenge because of the toxicities of systemic medications. This has led to the investigation of light-based technologies for safe and effective alternative treatment modalities. OBJECTIVE: The purpose of this study was to determine the safety and efficacy of 4 treatments with a 1,320-nm neodymium:yttrium aluminum garnet (Nd:YAG) laser in improving the appearance of onychomycosis. MATERIALS AND METHODS: This study was a 24-week, single-center randomized placebo-controlled study. Ten subjects were enrolled with culture-proven, bilateral great toenail onychomycosis. The subjects received 4 treatments with the 1,320-nm Nd:YAG laser to the treatment toenail on Days 1, 7, 14, and 60. The control toenail received a sham treatment of cryogen cooling only. Mycologic cultures were obtained at 3-month follow-up visits. RESULTS: Fifty percent of mycologic cultures were negative at the 3-month follow-up after 4 laser treatments. Toenails had improvement in subungual debris, hypertrophy, and yellowing. Patient satisfaction was upheld as assessed by the Nail Quality of Life Questionnaire. CONCLUSION: The 1,320-nm Nd:YAG laser may be a safe and effective therapy for improving the appearance of onychomycosis. Additional therapy may be necessary to enhance long-term results. Further investigation needs to explore the optimal treatment settings and the most effective treatment schedule.