Background Unsatisfactory treatment results for severe atopic dermatitis have led to many experimental therapies, including cromolyn sodium in various vehicles at concentrations ranging form 1% to 10%. Results suggest that the vehicle used to deliver the cromolyn is relevant to its effectiveness. Objective To test the efficacy of low concentrations of cromolyn in a water-soluble vehicle in the treatment of moderate-to-severe atopic dermatitis in a double-blind, placebo-controlled study. Methods Twenty-six pediatric patients who had failed to respond to conventional therapy were randomized into 2 treatment groups: patients in group A used the study drug for 1 month (phase I), then received the placebo for 1 month (phase II); and patients in group B used the placebo for 1 month, then received the study drug for 1 month. The study drug was cromolyn sodium inhalation solution mixed into a water-based emollient cream to a final concentration of 0.21%. Upon enrollment and at each follow-up visit, every patient was given a severity score based on extent and severity of skin involvement. Results At enrollment, there were no significant differences between groups A and B in severity scores, ages, sex, race, skin test and/or RAST positivity, eosinophil levels, IgE concentrations, or the presence of concomitant rhinitis or asthma. After the first phase of the study treatment, severity scores had decreased significantly for both groups with a significant difference between group A (cromolyn) and group B (placebo). After crossover, both groups had significantly lower severity scores than at entry into the study. Conclusion Treatment with topical cromolyn in a hydrophilic emollient vehicle has a significant anti-inflammatory effect on moderate-to-severe atopic dermatitis. We have now incorporated this treatment into our clinical practice.