The purpose of the present study is to ascertain the immunorestorative effect of two different drugs on immunodepression induced by small bowel surgical resection in an experimental model. The potential immunorestorative effect has been measured by the ability of the drug to avoid the delay of skin allograft rejection induced by surgery and the inhibition of CD4/CD8 index changes induced by surgery in spleen tissue. 120 Wistar-Furth rats (age 12–16 weeks) anesthetized with a single intramuscular dose of ketamine (25 mg), diazepine (4 mg) and atropine (0.1 mg) were allotted to two main groups. One group received a skin graft (SG) from Fisher 344 rats and was treated with placebo, Inmunoferón® (AM-3 polypeptidic drug) or TP-II (thymostimulin) before the experiment (groups I, II, III) or treated with placebo, Inmunoferón or TP-1 before the experiment and underwent enterectomy and anastomosis (groups IV, V, VI). On the 2nd, 5th and 8th postoperative days, biopsies of the SG were taken and the signs of rejection were microscopically studied and evaluated by a pathologist as zero, incipient, moderate or massive. The other group was treated similarly, but the animals did not receive a SG and were splenectomized 5 days later. CD4 and CD8 lymphocyte subpopulations were identified by means of immunoperoxidase technique and monoclonal antibodies. Thymostimulin is able to stimulate the presence of SG rejection signs on the 2nd postoperative day in nonenterectomized animals and on the 8th postoperative day in enterectomized rats and is able to avoid the decrease of the CD4/CD8 index in spleen tissue after surgical immunodepression. AM-3 has less effect on the presence of SG rejection signs and CD4/CD8 index than thymostimulin.