Onychomycosis is a common, chronic fungal nail infection that can have a significant negative impact on patients' physical and social functioning and emotional well-being. This study was undertaken to assess health-related quality of life (HRQoL) in patients with toenail onychomycosis. The Onychomycosis QoL questionnaire (ONYCHO), as a disease-specific instrument, and the Short Form 36 Health Survey (SF-36) as a generic instrument, were applied in 140 consecutive patients affected by onychomycosis. Women and patients who were experiencing toenail onychomycosis for more than 2 years were reporting worse disease-specific HRQoL. The patients working in blue-collar occupations and patients with greater involvement of individual nails were more affected by onychomycosis regarding symptoms. The results of this study confirm that although onychomycosis is not a life-threatening disease, it can significantly reduce patients' QoL.