Summary Background Nd:YAG lasers could be a safe and effective treatment modality for onychomycosis, without the side effects of drugs. Long and short‐pulsed Nd:YAG lasers were used in this clinical study in a side‐comparison manner without removal of onychomycotic nail material before treatment. Patients and Methods Big toenails of 10 patients were treated twice in a side‐comparison manner with the short‐pulsed Nd:YAG laser. Fungal cultures were taken and a histological examination was performed before treatment and after 9 months. Two independent investigators rated clearance using the “Onychomycosis Severity Index (OSI)” and standardized photographs at 3‐month intervals. Results OSI‐Scores decreased for 3.8 (15 %; p = 0.006), 4.8 (19 %; p = 0.0002) and 2.9 points (12 %; p = 0.04) within 3, 6 and 9 months. The positive culture rate at 9 months was significantly reduced to 35 % (p = 0.0003). Classification of severity of onychomycosis showed no change. The difference between the treatment regimens was not significant. Conclusions These results suggest that treatment of onychomycosis with the Nd:YAG laser without removing mycotic nail material can lead to a temporary clinical improvement, a reduction of positive fungal cultures and an improvement of the Onychomycosis Severity Index. The treatment regimen should be optimized to be used as an effective antimycotic monotherapy.