Background: Onychomycosis is fungal infection of the nail units caused by dermatophytes, molds or yeasts. Onychomycosis accounts for 50% of all nail diseases, representing a significant cosmetic concern. Topical antifungals are of limited efficacy owing to their poor absorption. Tazarotene was occasionally used as an off-label treatment for onychomycosis. Aim: Based on the immune-modulating and anti-inflammatory activity of tazarotene, we aimed to test the activity of tazarotene 0.1 % gel against fungi isolated from patients suffering from onychomycosis, and comparing it to another antifungal drug of moderate efficacy, tioconazole 28%. Methods: Seventy patients with confirmed clinical and laboratory diagnosis of onychomycosis were enrolled in the study. Patients were treated with either tazarotene 0.1% gel or tioconazole 28% solution for 12 weeks. Follow-up of the patients was done after 3 months of the therapy stoppage. Determination of the onychomycosis severity based on the onychomycosis severity index and mycological studies were done at week 0 and 24. Antifungal susceptibilitytesting of tazarotene against the isolated fungi was done. Results: Tazarotene showed antifungal activity manifested by induction of a mycological cure in 25.7 % of cases; however, this effect was comparable to Tioconazole 28%. Tazarotene showed a good efficacy against Aspergillus niger in vitro.  Conclusion: Tazarotene 0.1 % gel has antifungal activity comparable to tioconazole 28% solution in treating onychomycosis. They both achieved mycological cure in about 25% of cases. Aspergillus niger was the most sensitive species to tazarotene. Tazarotene could be prescribed as an adjuvant to the standard antifungals for treatment of onychomycosis.