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Background: Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture. The treatment decision requires balancing initial morbidity and costs of surgery against its potential long-term benefits over needle fasciotomy and collagenase., Objective: To compare the effectiveness of surgery, needle fasciotomy, and collagenase injection at 3 months and 2 years (secondary time points of the trial)., Design: A multicenter, randomized, outcome assessor-blinded, superiority trial. (ClinicalTrials.gov: NCT03192020)., Setting: 6 public hospitals in Finland., Participants: 302 persons with treatment-naive Dupuytren contracture (contracture angle <135°)., Intervention: Surgery ( n  = 101), needle fasciotomy ( n  = 101), or collagenase ( n  = 100)., Measurements: The primary outcome was the success rate, defined as greater than 50% contracture release and patients reaching the patient acceptable symptom state. Secondary outcomes included hand function, pain, quality of life, patient satisfaction, residual contracture angle, finger flexion, risk for retreatment, and serious adverse events., Results: A total of 292 (97%) and 284 (94%) participants completed the 3-month and 2-year follow-ups. Success rates were similar at 3 months: 71% (95% CI, 62% to 80%) for surgery, 73% (CI, 64% to 82%) for needle fasciotomy, and 73% (CI, 64% to 82%) for collagenase. At 2 years, surgery had superior success rates compared with both needle fasciotomy (78% vs. 50%; adjusted risk difference [aRD], 0.30 [CI, 0.17 to 0.43]) and collagenase (78% vs. 65%; aRD, 0.13 [CI, 0.01 to 0.26]). Secondary analyses paralleled with the primary analysis., Limitation: Participants were not blinded., Conclusion: Initial outcomes are similar between the treatments, but at 2 years success rates were maintained in the surgery group but were lower with both needle fasciotomy and collagenase despite retreatments., Primary Funding Source: Research Council of Finland., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1485.