SUMMARYAn investigation was made on the effects of donor‐host cross circulation on skin homograft rejection in the rat, a test being made of various histocompatibility barriers: F1, (F/344 × Lew) → F/344, F/344 &lrarr2; Lew, F/344 &lrarr2; Bf. We obtained the most significant prolongation of graft survival by grafting hybrid F1(F/344 × Lew) skin on F/344 cross circulated with Lew 2 days before. Positive results were obtained with the combination Lew &lrarr2; F/344 if the F/344 or Lew skin grafts were carried out 2 days after cross circulation. No effect was observed if the grafts were performed 22 days later, preceded by the i.v. injection of 5 × 107donor spleen cells. The administration alone of 108spleen cells resulted in a fair degree of activity in the F/344 → Lew combination and not vice versa. The results obtained with the strong histocompatibility barrier were contradictory. There was a slight increase of the mean survival time (MST) in the F/344 → Bf combination; on the contrary, a sensitizing effect in the Bf → F/344 combination was observed. These results are discussed and interpreted on the basis of the hypothesis that other factors besides the exchange of antigens intervene in cross circulation.