A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane (n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping (n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes–Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes–Weinstein monofilament examination. The ratio (percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00％ and 94.44％, respectively, with no significant difference between the two groups. There were no significant differences in the results of routine blood tests, liver and renal function tests, coagulation function tests, or immunoglobulin tests at 14 and 180 days postoperatively between the two groups. These findings suggest that the novel nerve matrix membrane is similar in efficacy to the commercially-available bovine-derived collagen membrane in the repair of peripheral nerve injury, and it may therefore serve as an alternative in the clinical setting. The clinical trial was approved by the Institutional Ethics Committee of Beijing Jishuitan Hospital, China (approval No. 20160902) on October 8, 2016, the Institutional Ethics Committee of the First Bethune Hospital of Jilin University, China (approval No. 160518-088) on December 14, 2016, and the Institutional Ethics Committee of Yantai Yuhuangding Hospital, China (approval No. 2016-10-01) on December 9, 2016. The clinical trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000033324) on May 28, 2020.