Until recently, the transplantation of skeletal muscle across a major histocompatibility barrier has proved difficult. However, with the advent of cyclosporine (CsA), it has become possible to achieve extended survival across such histocompatibility barriers. To date, very little is known about the histochemical, biochemical, immunological or contractile properties of long-term-surviving muscle allografts. Consequently, it was the focus of this study to histochemically examine muscle allografts prolonged with CsA and determine the cross-sectional area of fast glycolytic muscle fibers. Measurements of cross-sectional area were made because they are an important correlate to the amount of tension a muscle can generate. Animals were assigned randomly to one of three groups: control (normal) (n = 5), syngeneic (n = 4), and allogeneic (n = 4). Muscle allografts were performed by transplanting the gastrocnemius of an ACI rat (RT1a) hindlimb into the hindlimb of a Lewis rat (LEW;RT1(1]. The syngeneic model consisted of an ACI-to-ACI transplant. Animals in the allograft group were given CsA (8 mg/kg/day) until the time of sacrifice. At approximately 100 days following transplantation, both syngeneic and allogeneic muscles were removed from the recipient, and quickly frozen in isopentane cooled by liquid nitrogen. Muscle fibers were classified as slow-oxidative (SO), fast-oxidative-glycolytic (FOG), or fast-glycolytic (FG) based upon their staining for myofibrillar ATPase and NADH-dehydrogenase. From each muscle, the cross-sectional area of approximately 175 FG muscle fibers was determined. The fast-glycolytic muscle fibers of both the syngeneic and allogeneic grafts demonstrated a substantial decrease in cross-sectional area. The mean value (+/- SD) for the fibers of the allografted muscle was 1165 +/- 533 microns 2. The mean (+/- SD) fiber cross-sectional area for the fibers of the syngeneic muscle was 973 +/- 421 microns 2. These values contrast with a mean (+/- SD) value of 3552 +/- 601 microns 2 for fibers from age-matched control animals. The differences between the syngeneic and allogeneic muscles were not significant (P greater than 0.05). However, both exhibited significant (P less than 0.01) atrophy compared with the control muscle.