Introduction <p>Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL), a malignant and chronic skin disease. Early-stage MF has a generally favorable prognosis, but effective and well-tolerated skin-directed therapies are crucial for management. HyBryte™ is a photodynamic therapy of topical hypericin that was recently shown to be well tolerated and efficacious in early-stage CTCL. Valchlor^® (mechlorethamine) is an approved second-line therapy for use in early-stage CTCL after other topical therapies. This study compared Valchlor^® to HyBryte™ following 12&#xa0;weeks of treatment. The objectives in this study were (i) to obtain preliminary comparative assessment of safety and efficacy of Valchlor^® versus HyBryte™ through 12&#xa0;weeks of treatment, and (ii) to better understand the impact of HyBryte™ application on the measurement of modified Composite Assessment of Index Lesion Severity (mCAILS).</p> Methods <p>This was an open-label trial enrolling 10 patients with CTCL (stage&#xa0;IA, IB, or IIA) randomized 1:1 to receive topical HyBryte™ or topical Valchlor^® for 12&#xa0;weeks.</p> Results <p>The overall response rate (ORR, i.e., complete responders + partial responders) was 60% (3/5) in the HyBryte™ treatment group and 20% (1/5; not significant) in the Valchlor^® treatment group over 12&#xa0;weeks. HyBryte™ demonstrated no local adverse events at application sites, while 60% (3/5) of patients treated with Valchlor^® had skin reactions, including one case which led to study withdrawal.</p> Conclusions <p>This is a single-center, open-label study. It is a pilot study requiring additional research to confirm its results. This study demonstrated the favorable safety and efficacy profile of HyBryte™ compared to Valchlor^® in patients with CTCL. HyBryte™ showed higher treatment success rates and was better tolerated.</p> Trial Registration <p>ClinicalTrials.gov, NCT06149247; registered November 20, 2023.</p>