Treating nail psoriasis is often a time-consuming challenge with an unsecure outcome. Response to the treatment is variable and relapses are common. Systemic treatments have multiple systemic side effects and lack of the patient compliance makes intra-lesional therapies not the best choice for treatment of nail psoriasis. We aimed to evaluate and compare the efficacy and side effects of methotrexate versus calcipotriol plus betamethasone two-compound formula when applied topically to psoriatic nails after fractional CO2laser. This comparative pilot study included 20 patients with nail psoriasis. One side was treated with fractional CO2laser followed by the application of topical methotrexate (Group A) and the other side with fractional CO2laser followed by topical (Calcipotriol 0.05 mg/gm + Betamethasone 0.5 mg/gm) (Group B). 4 sessions were done, once every 2 weeks. There was a high statistical significant decrease in total NAPSI score in group A at 1(P= 0.000) and 2 months (P= 0.000). There was a high statistical significant decrease in total NAPSI score in group B at 1(P= 0.001) and 2 months (P= 0.001). There was no statistical significant difference regarding total NAPSI score between both group A and B at 0 (P= 0.271), 1(P= 0.513) and 2 months (P= 0.647). Combined fractional CO2laser with either topical MTX or topical betamethasone plus calcipotriol two-compound formula is effective treatment for nail psoriasis.