Nickel-titanium shape memory alloy (Nitinol) has properties that could be very useful in surgical applications. Thermal shape memory, superelasticity, and high damping properties make such alloys behave differently compared to other implant metals. There has previously been a lack of sufficient evidence on the biocompatibility of Nitinol. The purpose of this study was to evaluate general soft tissue response and biocompatibility to Nitinol in vivo, and to clarify neural and perineural responses, previously unreported. Seventy-five rats were randomized into three groups. Test specimens were implanted into paravertebral muscle and near the sciatic nerve. A comparison was made between Nitinol, stainless steel, and Ti-6Al-4V. The animals were euthanized at 2, 4, 8, 12, and 26 weeks after implantation. General morphologic and histologic observations were made under light microscopy. Semiautomatic computerized image analysis was used to measure the encapsule membrane thickness around the implants. The muscular tissue response to Nitinol was clearly nontoxic, regardless of the time period. The overall inflammatory response to Nitinol was very similar to that of stainless steel and Ti-6Al-4V alloy. There were no necroses, granulomas, or signs of dystrophic soft tissue clacification. The immune cell response to Nitinol remained low. Only a few foreign-body giant cells were present. The detected neural and perineural responses were also clearly nontoxic and nonirritating with Nitinol. No qualitative differences in histology between the different test materials could be seen. At 8 weeks, the encapsule membrane of Nitinol was thicker than that of stainless steel (mean 62 +/- 25 microns vs. 41 +/- 8 microns). At the end of the study, the encapsule thickness was equal to all the materials tested. We concluded that Nitinol had good in vivo biocompatibility after intramuscular and perineural implantation in rats in the 26-week follow-up. Based on the results of the present study, Nitinol appears to have good potential for clinical use.