Objectives. Onychomycosis is a fungal infection of the nail bed, nail matrix, and nail plate. Lasers have recently been studied as future clinical options for onychomycosis. We sought to evaluate the efficacy of the long-pulsed Nd:YAG 1064-nmlaser on onychomycosis using a two-stage treatment. Methods. A total of 100 affected nails (88 toenails and 12 fingernails from 22 patients) were treated using a long-pulsed Nd:YAG1064-nm laser. The self-controlled treatment schedule included the first stage (1 session per week for 8 weeks) and the second stage (1 session every 4 weeks for 16 weeks). Patients were followed up with for 12 weeks after the last laser treatment. Direct microscopy, cultures, and clinical assessments were performed at various time points. Results. Of the nails studied, 84% were infected by Trichophyton rubrum, while others were coinfected with T. rubrum and other fugal strains. The mycological clearance rate and the clinical efficacy rate of the nails were 29% and 21% after the first stage, 69% and 35% after the second stage, and 67% and 39% during follow-up, respectively. The second stage of laser treatment significantly improved the mycological clearance and clinical efficacy. Conclusion. Long-pulsed Nd:YAG 1064-nm laser two-stage treatment was effective for onychomycosis, with significantly improved mycological clearance and clinical efficacy.