Mycosis fungoides (MF) represent the most frequent form of cutaneous T-cell lymphoma (CTCL). Chlormethine gel has been approved as first-line therapy in MF. The classification of early forms of MF is clinically and histologically complex even for experienced clinicians. Ultra-high-frequency ultrasound (UHFUS) is a new non-invasive method that is capable of supporting clinical evaluation, thus providing both a diagnostic guide for distinguishing different stages of the disease and a therapeutic method in terms of monitoring the treatment. In our case report, we clinically and ultrasonographically evaluated the efficacy of chlormethine gel treatment on patches resistant to previous local treatments. A 63-year-old patient was treated for MF stage 1B with cycles of topical clobetasol cream and PUVA and UVB narrow-band phototherapy for 2 years, with a partial therapeutic response. Patches remained at the level of the left and right hips and lower legs. The patient began treatment with chlormethine gel 3 times a week for 2 months. We performed clinical and ultrasound evaluations on the left hip at baseline and after 2 months. The ultrasound examination was performed using (VEVO MD, VisualSonics), both in B-mode and C-mode, with a 70 MHz frequency probe. At baseline, we found a hypoechoic band of 0.94 mm named the Subepidermal Low Echogenity Band (SLEB), localized under the dermo-epidermal junction. Multiple dilated hair follicles with vascular invasion, disrupting the dermo-epidermal junction, and numerous vascular lacunae at the dermal level were found using C-mode. After 2 months of treatment, the lesions had clinically healed with the persistence of a pigmentary outcome. UHFUS identified minimal thickness of the SLEB and minimal vascularization. Chlormethine gel was an effective and well-tolerated treatment in patches unresponsive to other topical treatments. The use of a non-invasive diagnostic technique can allow objective assessment of lesions with a better therapeutic approach.