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Introduction: Psoriasis is a common inflammatory skin disease that significantly impacts patients' psychosocial wellbeing. Despite increasingly effective treatment options, the recurrence of plaques after discontinuation of therapy in many patients highlights the need for additional therapies. Methods: We report two cases of patients with concurrent psoriasis and mycosis fungoides who were treated with topical mechlorethamine (MCH). A literature review was performed by searching PubMed using the keywords psoriasis, mechlorethamine, chlormethine, and nitrogen mustard. Results: Both patients had significant improvement in their psoriasis following treatment with topical MCH gel, which was well tolerated and maintained clearance after 1 and 3 years of follow-up. Seven prospective cohort studies investigating the use of topical MCH were identified through literature review. Out of five studies reporting clinical outcomes by patient, 68 of 77 patients (88%) experienced an improvement in their psoriasis, with 47 of 77 (61%) achieving complete or near-complete clearance. The remaining two studies reported clinical outcomes by lesion, demonstrating improvement in 40 of 45 lesions (88%) and complete or near-complete clearance in 32 of 42 lesions (76%). Contact dermatitis was the most frequent adverse effect, observed in 56 of 125 patients (45%). Conclusions: Topical MCH may be an option for patients with psoriasis who fail or have incomplete responses to other treatments. Published studies are limited by lack of standardized treatment regimens and well-defined outcome measures, highlighting the need for prospective clinical trials to better understand the utility of this topical agent in psoriasis.