Onychomycosis is a chronic fungal infection of the nails that accounts for10% of the population worldwide and about 50% of the nail diseases in clinical practice. It has negative impact on patient's quality of life. Multiple treatments are introduced to treat onychomycosis but they are limited by high cost, side effects, drug interaction, and reduced transungual delivery. We aimed to investigate the safety and efficacy of calcipotriol 0.005% cream versus terbinafine hydrochloride 1% cream in treatment of onychomycosis. Twenty adult patients with bilateral onychomycosis were randomized. Twenty adult patients with bilateral onychomycosis were randomized in this study. The patients received calcipotriol 0.005% cream on one side and terbinafine hydrochloride 1% cream on the other side twice/day for 3 months. Outcome was evaluated after treatment by onychomycosis severity index (OSI), mycological evaluation, investigator's assessment and patient's satisfaction. Side effects were also evaluated. Study registration number (IRB approval number M602, 30/8/2022). Calcipotriol 0.005% cream had significant higher degree of improvement after 3-month treatment of onychomycosis compared to terbinafine hydrochloride 1% cream (p value = 0.02), while calcipotriol had significantly higher side effects in terms of tolerable irritation compared to terbenafine (p value <
0.05). Insignificant differences between both sides were found regarding post treatment OSI, investigator's assessment and patient's satisfaction (p value = 0.12, 0.73, 0.22 respectively). This pilot study provided preliminary data for significant superiority of calcipotriol 0.005% cream in treatment of onychomycosis regarding degree of improvement after 3-month treatment compared to terbinafine hydrochloride 1% cream. Irritation induced by calcipotriol 0.005% cream was tolerable by the patients. Further studies are still needed.