Extraneural scar reduction is an important goal in peripheral nerve microsurgery. The use of biosynthetic materials, such as Seprafilm , reduces postoperative adhesions in abdominopelvic gynecologic and orthopedic surgery. The study evaluates the safety of Seprafilm in proximity to nerve tissue in a noninjury (phase 1) and injury (phase 2) model. Phase 1 groups were: (1) sciatic nerve exposure and neurolysis (n = 15), (2) Seprafilm placement superficial to the nerve (n = 15), and (3) circumferentially wrapping Seprafilm around the nerve (n = 15). Outcome measures at 45 and 90 days included wound inspection, histomorphometry, and stereological analysis of vascularity. Phase II groups were: (1) sciatic nerve cut and repair alone (n = 15) or (2) nerve wrapped with Seprafilm (n = 15). Nerves were evaluated at 18, 32, and 42 days postoperatively, and animals underwent biweekly functional walking tracks. In phase I, no significant differences were detected between groups. In phase II, fewer perineural scar bands were seen with Seprafilm . Histomorphometric differences favoring Seprafilm at 18 days and favoring control at 42 days were noted ( P < 0.05), though no differences in functional outcomes were detected. Qualitatively less perineural scar tissue was seen when using Seprafilm . No functional or histological deleterious effects were noted from placing Seprafilm on intact nerves or cut and repaired nerves.