Atopic dermatitis (AD) is a result of complex genetic, epigenetic, environmental, and immunological interactions with an overlapping epidermal barrier defect. The study evaluates the efficacy and tolerability of topical Vitamin B12‐barrier cream (MB12) compared with standard glycerol‐petrolatum‐based emollient cream (GPC) used three times a day for mild AD. The study was conducted as a on one hemi‐body randomized, controlled, single‐blind, intra‐patient left‐to‐right comparative trial by patients with clinical diagnosis of mild AD measured with total SCORAD index over 4 months. MB12 was compared on one hemi‐body treated (GPC). The comparisons of score values were performed primarily by using non‐parametric procedures: Mann–Whitney‐U test (for independent samples) and Wilcoxon test (for dependent samples). All 22 patients were randomized (left or right side treated with MB12 or GPC). At week 12 a reduction from baseline in SCORAD index was assessed in both body sites with 77.6% SCORAD index reduction in the MB12 treated body sites versus 33.5% in the GPC treated body sites. These results suggest that MB12 could represent a new option in the treatment of mild AD.