Severe alopecia areata (AA) may have a chronic relapsing course and is often resistant to current treatments. Objectives: The aim of our study was to evaluate whether topical immunotherapy with squaric acid dibutylester (SADBE) is able to improve the course of severe AA and to reduce the severity of relapses. Methods: Fifty-four patients affected by severe AA treated with SADBE who were followed for a period of at least 2 years were selected as the study group. Data collected were compared with those of a matched control group of 54 patients who did not receive any treatment. Student's t-test, analysis of variance (ANOVA) and Pearson's chi-squared test were utilized for data analysis. Results: At the end of therapy, in comparison with the control group, the treatment group showed a statistically significant (p<0.001) improvement. At follow-up, there was no significant change in relapse rate (treated 44% vs control 52%). However, relapses in the treated group were significantly less severe compared with the control group (p<0.001). Conclutions: Our data suggest that topical SADBE represents a valid therapeutic option in severe AA, and may prove to be disease modifying.