This prospective study aimed to compare the intraosseous (IO) and intravenous (IV) effects of propofol on selected blood parameters and physiological variables during general anesthesia in rabbits. Thirty New Zealand White rabbits were studied. Six rabbits received IV propofol (group 1) and another 6 rabbits, were injected propofol intraosseously (Group 2) for 30 minutes (experimental groups). Rabbits of the third and fourth groups received IV and IO normal saline at the same volume given to the experimental groups, respectively. In the fifth group IO cannulation was performed but neither propofol nor normal saline were administered. Blood profiles were assayed before induction and after recovery of anesthesia. Heart and respiratory rates, rectal temperature, saturation of peripheral oxygen and mean arterial blood pressure were recorded. Heart rate increased significantly 1 to 5 minutes after induction of anesthesia in experimental groups (P < 0.05). Although mean arterial blood pressure decreased significantly from baseline, values remained above 60 mm Hg (P < 0.05). Respiratory rate decreased significantly in experimental groups, but remained higher in group 2 (P < 0.05). The lymphocyte count decreased significantly in group 1 (P < 0.05). The concentration of alkaline phosphatase in all rabbits, aspartate aminotransferase and gamma-glutamyl transferase in the first group and gamma-glutamyl transferase in the third group increased significantly (P < 0.05). Total bilirubin decreased significantly in group 2 (P < 0.05). All measured values remained within normal limits. Based on the least significant physiological, hematological and biochemical effects, the IO injection of propofol appears to be safe and suitable method of anesthesia in rabbits with limited vascular access.