Intimal hyperplasia (IH) is the precursor of vein graft (VG) atherosclerosis. Collagens are a family of genetically distinct proteins which accumulate during the development of IH and VG atherosclerosis. Using immunohistochemical techniques, we examined changes in collagen III (fibrillar) and IV (basement membrane) protein expression following interpositional venous bypass grafting in rabbits. Control jugular veins (CV, n = 6) and VGs harvested 3 days (n = 6), 7 days (n = 3) and 28 days (n = 4) after surgery were studied to represent different stages in the development of IH. The specificities of the anticollagen antibodies were confirmed on histologic sections of rabbit skin. In CV, collagen IV was expressed over the entire (100%) intima. In the 3 day VG (pre-IH), collagen IV was expressed over approximately 50% of the intimal area and was notably absent in regions of inflammatory infiltration. In the 7 day VG (early IH), collagen IV was entirely absent in the intima, but, in the 29 day VG (maximal IH) collagen IV was expressed over most (> 75%) of the area of intima. In striking contrast, collagen III was absent in the intima of the control, 3 day and 28 day VGs but was faintly detected in the intima of the 7 day VG. In conclusion: Collagen subtypes express different patterns of change in response to venous bypass grafting. In particular, collagen IV demonstrates dramatic alterations in protein expression during the formation of IH which may provide unique targets for therapy.