Objectives. To determine the effect of long-term experimental hypercholesterolemia on cavernosal tissues and to evaluate whether these alterations are reversible after improvement of hypercholesterolemia. Methods. Thirty-seven New Zealand male rabbits with a mean age of 5 to 6 months and a weight of 2 to 2.5 kg were included in this study. The control group (group 1, n = 7) was fed with normal standard rabbit chow for 24 weeks, the hypercholesterolemia group (group 2, n = 17) was fed with a 1% pure cholesterol diet for 24 weeks, and the reversibility group (group 3, n = 13) was fed first with the 1% pure cholesterol diet for 24 weeks and then with normal standard rabbit chow for 12 weeks. The basal and 24-week serum lipid profiles of all groups and the 36-week serum lipid profiles of group 3 were measured. Core tissue samples 4 mm in diameter taken from formalin-fixed, paraffin-embedded tissue blocks of rabbit corpus cavernosum were examined for Masson trichrome histochemically and desmin and smooth muscle actin by the tissue array method using immunohistochemistry. Results. Hypercholesterolemia was observed in groups 2 and 3 at 24 weeks compared with group 1. In group 3, at 36 weeks, the cholesterol levels were decreased. A statistically significant (P <0.05) irreversible decrease was observed in smooth muscle actin level in group 3 (reversibility group) by immunohistochemical analysis. The decrease in desmin was reversible, and no significant difference was observed in collagen among the three groups. Conclusions. Long-term chronic effects of experimental hypercholesterolemia on cavernosal smooth muscles might be irreversible and this might alter erectile function. © 2006 Elsevier Inc.