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Local disruption of the cord that causes contracture of the finger in Dupuytren disease can be achieved either through mechanical division by percutaneous needle fasciotomy (PNF) or through enzymatic digestion by injectable collagenase Clostridium histolyticum (CCH). This study was designed to compare clinical and patient-reported outcomes between patients who had been treated with each method.A prospective, randomized, single-blinded, controlled trial was designed and included 156 patients with a contracture of the metacarpophalangeal (MCP) joint of ≥20°. The patients were allocated to treatment with either PNF or CCH. The primary outcome was a reduction of the MCP contracture to <5°. Secondary outcomes included the reduction of any concomitant contracture of the proximal interphalangeal (PIP) joint, the presence of Dupuytren cords, and changes in patient-reported outcomes as measured with the URAM (Unité Rhumatologique des Affections de Main) and QuickDASH (an abbreviated version of the Disabilities of the Arm, Shoulder and Hand [DASH]) questionnaires and visual analog scales for patient satisfaction. All treatments were performed by a single surgeon and all blinded follow-up measurements were made by a single physiotherapist. The participants were assessed at 1 week, 6 months, and 1 and 2 years after the interventions.A total of 152 patients (97%) were examined at 2 years, at which time 58 patients (76%) treated with CCH and 60 (79%) treated with PNF retained a straight MCP joint. No cords were detectable in >50% of the patients at 2 years. There were no significant differences in the reduction of PIP contracture, range of motion, or patient-reported outcomes between the 2 treatments.This trial demonstrated no advantage of CCH treatment compared with PNF in terms of clinical outcome at any time during the 2-year follow-up. The significant decrease in the number of pathological cords (p < 0.0001, Wilcoxon signed-rank test) after disruption regardless of the method used may indicate that resorption of pathological collagen occurs when the tension in the Dupuytren cord is diminished.Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.