BACKGROUND Intralesional methotrexate (il-MTX) has been used as neoadjuvant therapy for cutaneous squamous cell carcinoma (cSCC) but studies on its effects on tumor thickness are lacking. OBJECTIVE The objective of this study was to evaluate il-MTX response with ultrasound examination. METHODS The authors conducted a prospective study in 40 patients with histologically confirmed cSCC. Neodjuvant il-MTX therapy was administered before surgery. Ultrasound evaluation was performed before the first infiltration and before surgical treatment. RESULTS Response to neoadjuvant treatment was observed in 92.5% of patients, both clinically and sonographically. There was a good correlation between both types of measurements, with r = 0.892 for the minor diameter and r = 0.944 for the major diameter ( p < .001). The authors found an ultrasound overestimation compared to the clinical measurements in 92.5% of patients (mean overestimation: 1.08 mm). There was a good correlation between ultrasound and histological measurements in tumor thickness with r = 0.932 ( p < .01), with an ultrasound overestimation in 97.5% of cases (mean overestimation: 0.90 mm). CONCLUSION Neoadjuvant il-MTX can reduce not only surface tumor dimensions but also tumor thickness. Ultrasound improves treatment response control with greater accuracy than clinical assessment alone.