Safety was evaluated for collagenase Clostridium histolyticum (CCH) based on 11 clinical trials (N = 1082) and compared with fasciectomy data in a structured literature review of 48 European studies (N = 7727) for treatment of Dupuytren’s contracture. Incidence of adverse events was numerically lower with CCH vs. equivalent complications from fasciectomy (median [range] incidence), including nerve injury (0% vs. 3.8% [0%–50+%]), neurapraxia (4.4% vs. 9.4% [0%–51.3%]), complex regional pain syndrome (0.1% vs. 4.5% [1.3%–18.5%]) and arterial injury (0% vs. 5.5% [0.8%–16.5%]). Tendon injury (0.3% vs. 0.1% [0%–0.2%]), skin injury (16.2% vs. 2.8% [0%–25.9%]) and haematoma (77.7% vs. 2.0% [0%–25%]) occurred at a numerically higher incidence with CCH than surgery. Adverse events in CCH trials not reported after fasciectomy included peripheral oedema; extremity pain; injection site pain, haemorrhage and swelling; tenderness; pruritus and lymphadenopathy. CCH-related adverse events were reported as predominantly injection-related and transient. These results may support clinical decision-making for treatment of Dupuytren’s contracture.