Autologous bone is the preferred bone graft material because it carries proteins as bone-enhancing substrates, minerals, and vital bone cells. Calcium sulfate (CS) is a well-tolerated, biodegradable, osteoconductive bone graft substitute and is a reasonable alternative to autogenous bone graft. Blood vessels are an important component of bone formation and maintenance. The process of vascular induction is called angiogenesis, and it plays a key role in all regenerative processes. Bone tissue differentiation is related to the local presence of blood vessels. One method to evaluate the presence of blood vessels in a tissue is to count the microvessels to evaluate microvessel density (MVD). The aim of the present study was to conduct a comparative evaluation of microvessel density in sites treated with CS and autologous bone in rabbits, with or without e-PTFE nonresorbable membranes (Gore-Tex, Flagstaff, Ariz). Nine New Zealand rabbits, each weighing about 2.5 kg, were used in this experiment. Three 6-mm wide defects were created in each tibial metaphysis. The defects were filled in a random way. The defects of group 1 (3 rabbits) were filled with CS granules (Surgiplaster, Classimplant, Rome, Italy) and covered with e-PTFE membranes. The defects in group 2 (3 rabbits) were filled with CS granules (Surgiplaster). The defects in group 3 (3 rabbits) were filled with autologous bone. A total of 54 defects were filled (18 with CS and e-PTFE membranes, 18 with CS alone, and 18 with autologous bone). No postoperative deaths or complications occurred. All nine animals were sacrificed at 4 weeks. MVD results were as follows: in the first group, 9.88 ± 4.613; in the second group, 7.92 ± 1.998; and in the third group, 5.56 ± 1.895. P = .000 was highly significant. Statistically significant differences were found between groups 1 and 3, 1 and 2, and 2 and 3. The presence of more blood vessels in the sites treated with CS could help to explain the good results reported in the literature with the use of CS.