Background: Treatment of acanthosis nigricans (AN) is challenging, and new modali- ties are being explored continuously to increase the therapeutic efficacy. Aim: To evaluate the efficacy and safety of fractional CO2 laser compared to trichlo- roacetic acid (TCA) peel in the treatment of pseudo-acanthosis nigricans (pseudo-AN). Methods: The study included 40 patients with pseudo-AN on the neck and axilla al- located into two groups each containing 20 patients. Group (A) was treated with TCA 20% peel applied on the pigmented area while group (B) received fractional CO2 laser. Both treatments were performed till complete clearance or for a maximum of four treatment sessions. Patients with excellent response were further followed up for 6 months after the end of treatment. Results: Both modalities were effective in the treatment of pseudo-AN; however, the therapeutic response was significantly higher in the fractional CO2 laser group com- pared to the TCA peel group (p < 0.01). Marked to excellent response (51%–100% clearance of AN lesions) was achieved in 85% of the patients in the fractional laser group versus 10% of the patients in the TCA group. Adverse effects, for example, persistent erythema, post-inflammatory hyperpigmentation, and burning sensation, were also statistically higher in the TCA group compared to the laser group (p = 0.04). Conclusion: Fractional CO2 laser is a promising effective and well-tolerated treatment modality for pseudo-acanthosis nigricans.