Recent clinical evidence suggests that hylan, a modified hyaluronan, and related products potentially elicit foreign body granulomatous inflammation in human soft tissue. We investigated the biocompatibility of hylan G-F 20 (Synvisc) for up to 28 days after intradermal injection in guinea pigs and intramuscular injection in rabbits. Compared to saline and unmodified hyaluronan, hylan induced definitive macroscopic changes in guinea pigs by day 14 or later and in rabbits by 28 days after injection. Histologically, at the injection sites, there was severe granulomatous inflammation in guinea pigs and acute inflammation with minimal infiltration of macrophages and foreign body giant cells in rabbits. Furthermore, specific antibodies against hylan were demonstrated in guinea pigs by passive cutaneous anaphylaxis, and substantial deposits of IgG on hylan were evident by immunohistochemistry. The present results contradict previous reports on biocompatibility of hylan and suggest that hylan may potentially induce similar unfavorable reactions in humans.