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Background Nail psoriasis is a distressing clinical condition as it is known that psoriasis on visible areas of the skin, such as the face, hands and nails, may have a substantial negative impact on physical, psychological, and social dimensions of quality of life. The additional negative consequences of nail involvement in psoriasis are pain, inability to grasp small objects, tie shoe laces or button clothes, and cause an altered sense of fine touch. Objective To evaluate and compare the efficacy, safety and side effects of co2 laser combined with topical methotrexate in one side and topical (calcipotriol +betamethasone) in the other side of the patient for the treatment of nail psoriasis. Patients and Methods This comparative pilot study included 20 patients with nail psoriasis. They were recruited from the dermatology out-patient clinic of Ain–Shams University Hospitals, during the period from March 2019 till October 2019. The study was approved by Research Ethical Committee of Ain Shams University (FMASU M S 71/2019) and fulfilled all the ethical aspects required for a human research. Results Our study revealed that both medications showed marked statistical and clinical improvement of the nail condition in a period of 2 months when applied topically after nail exposure to fractional co2 laser which facilitated the delivery of both medications through the nail plates to the site of the psoriasis inflammation in therapeutic concentrations by creating pores through the nails. There was no statistical or clinical difference between both medications regarding the improvement of the NAPSI scores or the level of patient satisfaction. However, there were some nail symptoms that didn’t show any improvement as (sub-ungual hyperkeratosis and nail ridging). Conclusion Our treatment protocol’s side effects based mainly on the action of fractional co2 laser which caused pain and nail bleeding during sessions for some of the patients in each group, while topical methotrexate caused nail yellowish discoloration for the all involved group. However, these side effects lasted for very short time and didn’t have any impact on the level of the patient satisfaction. There was no statistical difference in the level of the patient satisfaction between both groups.