Background: Onychomycosis is a fungal infection of the nail plate and subungual area. In this study, we examined the efficacy of laser treatment using self-controlled study programs involving a long-pulsed Nd:YAG 1064-nm laser combined with oral medication. Methods: Self-controlled strategies were followed in this study. The patients received treatment with oral itraconazole in conjunction with long-pulsed Nd: YAG 1064-nm laser treatment at the nails of the unilateral limb once a week for a total of four times. A total of 84 affected nails were divided into Group A (mild to moderate) and Group B (severe) according to disease severity. Affected nails with the same Scoring Clinical Index for Onychomycosis scores were selected to compare the therapeutic effects of the pure medication treatment group and the combination treatment group with a 24-week follow-up period. Results: In Group A, at the 8th, 16th, and 24th weeks of follow-up, the efficacies in the pure medication treatment group were 81.0%, 81.0%, and 90.5%, respectively, while those in the combination treatment group were 100%, 95.2%, and 90.5%, respectively. The differences between groups were not significant (8th week: chi(2) = 4.421, P > 0.05; 16th week: chi(2) = 2.043, P > 0.05; 24th week: chi(2) = 0.00, P > 0.05). In Group B, at the 8th, 16th, and 24th weeks of follow-up, the efficacies in the pure medication treatment group were 61.9%, 66.7%, and 52.4%, respectively, while those in the combination treatment group were 95.2%, 90.5%, and 100%, respectively. The differences between groups at the 8th and 24th weeks of follow-up were statistically significant (8th week: chi(2) = 6.929, P < 0.05; 24th week: chi(2) = 13.125, P < 0.05). Conclusions: For patients with mild or moderate onychomycosis, we recommended a pure medication treatment or combination treatment with medication and laser. For those patients with severe onychomycosis, we recommended a combination of medication and laser therapy.