Background: Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking. Objective: Our objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting. Methods: This prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA–IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire. Results: In total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores. Conclusions: This real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life.