Background Treatment response for psoriasis is typically evaluated using clinical scores. However, patients can relapse after clinical clearance, suggesting persistent inflammation. Dermoscopy, reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) can non‐invasively improve treatment response assessment. Objectives To compare the clinical and non‐invasive microscopic features in a psoriatic target lesion treated with clobetasol cream or calcipotriol/betamethasone dipropionate foam (Cal/BD foam). Methods Prospective, unicentric, open, randomized clinical trial comparing clinical data total clinical score (TCS) and microscopic data (dermoscopy, RCM and OCT) in psoriasis patients treated with clobetasol or Cal/BD foam. Results We included 36 adult patients (22 men). At week 4, more patients treated with Cal/BD foam achieved TCS ≤1 than with clobetasol (63.2% vs. 18.8%, P = 0.016). Treatment satisfaction was higher with Cal/BD foam (P < 0.03). Microscopically, Cal/BD foam induced more reduction in epidermal thickness at week 4 (P < 0.049). Dilated horizontal blood vessels were more common with clobetasol than with Cal/BD foam at week 8 (69.2% vs. 31.2%, P = 0.159). If epidermal hyperplasia was noted at baseline, the response was poorer with clobetasol (P = 0.029). Limitations Small sample size, open study, imaging sampling bias. Conclusion Cal/BD foam is more effective than clobetasol, has better patient satisfaction and induces greater reduction in the hyperkeratosis/acanthosis, regardless of baseline epidermal hyperplasia.