BACKGROUND: Laser therapy can be used as an alternative treatment for onychomycosis; however, there are some limitations to its efficacy as a single agent. OBJECTIVE: To evaluate the effectiveness of combination therapy with 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser and topical efinaconazole in onychomycosis treatment and identify factors influencing the therapeutic outcomes of combination treatment. METHODS: Big toenails with onychomycosis were treated by 1,064-nm Nd:YAG laser at 4-week intervals with daily application of topical efinaconazole. Therapeutic response was assessed through onychomycosis severity index (OSI) and percentage of nail infected (PNI), and its association with a variety of factors that may affect treatment outcome was evaluated. RESULTS: One hundred big toenails were included in the study and significant clinical improvements were observed after treatment (OSI improvement score = 76.68 ± 28.83, PNI improvement score = 72.37 ± 30.37). There was no difference in treatment response according to the number of laser treatments, onychomycosis clinical type, or initial severity. However, patient age was negatively correlated with clinical improvement (p = 0.019). Also, female patients had better therapeutic responses than male patients. CONCLUSION: Combined treatment with Nd:YAG laser and topical efinaconazole has a significant therapeutic effect on onychomycosis. A randomized controlled trial is warranted in the future.