The mechanisms responsible for sclerotic-type chronic GVHD of the skin (ScGVHD) are unclear; however, platelet-derived growth factor (PDGF) and transforming growth factor-β (TGFβ) have been implicated. Imatinib mesylate is a tyrosine kinase inhibitor with activity against both PDGFR and TGFβ and an established safety profile for the treatment chronic myelogenous leukemia. However, its safety and efficacy in ScGVHD is unknown. 20 patients were enrolled in a Phase II study of imatinib mesylate for the treatment of ScGVHD. Eligible patients had ScGVHD limiting rangeof-motion (ROM) in at least 1 joint by >25%. Initially, patients were given 400mg (pediatric 260mg/m2) with dose reduction allowed for toxicity (cohort 1). Due to a high incidence of adverse effects, the study was amended to 100mg with escalation to 200mg daily at 1 month (cohort 2). The 6 month primary endpoint was percent ROM change at 1-3 target joints: partial response (PR) = >25% gain; progressive disease (PD) = >25% loss, or >1 steroid pulse per 3-month period; stable disease (SD) = all other. Secondary endpoints included toxicity, skin score, patient-reported quality of life and functional measures, serum drug concentrations (cohort 2), and other cGVHD organ response. At 6 months, two patients had PD, 5 PR, 7 SD, and 6 were non-evaluable. 11/14 (78.6%) evaluable patients had ROM improvement (mean gain 31%). No significant improvement was seen in other cGVHD manifestations. Adverse events included hypophosphatemia, GI upset, fatigue, muscle cramping, tinnitus and pulmonary edema. Mean steady-state serum drug concentration (1157ng/mL) in cohort 2 (200mg) was within the PDGFR inhibitory range. This data suggests that low-dose imatinib therapy has efficacy for ScGVHD; however, tolerability is a significant issue when utilized in patients with ScGVHD.