Intra-subject, left-right, randomized, controlled study designs are often used for proof-of-concept studies in dermatology. This design was used to evaluate the safety and efficacy of a topical solution of tofacitinib (NCT00678561), a small-molecule Janus kinase inhibitor under investigation for the topical and oral treatment of patients with chronic plaque psoriasis. Eighty-one patients, each with matched left and right target plaques, were randomized to 2%, 0.2%, or 0.02% tofacitinib or vehicle solution once or twice daily. Patients treated one plaque as per their randomization group (2%, 0.2%, 0.02% tofacitinib, or vehicle solution), and used vehicle to treat the contralateral plaque for 4 weeks. Except during clinic visits, study drug applications were performed unsupervised outside the clinical trial site. Intra-subject, vehicle-adjusted mean percent change from baseline in Target Plaque Severity Score at week 4 (primary efficacy endpoint) was not significantly different from baseline for any treatment group (P values of 0.28-0.68). However, skin biopsy analyses detected tofacitinib in both tofacitinib- and vehicle-treated plaques of some patients, suggesting cross-contamination or solution misapplication. Lack of efficacy with tofacitinib relative to vehicle may be due to the intra-subject study design with unsupervised applications. These findings have potential implications for future intra-subject studies of topical treatments.