The TP-5 pentapeptide analog of thymopoietin and the SP-5 pentapeptide analog of splenin, which differ only in substitution ofGluforAspand represent positions 32–36 of the parent molecules, were compared for effects on the capacity of C3H/HeJ female mice to reject C3H/HeJ male skin (the H-Y rejection response). The actions of these TP-5 and SP-5 analogs of respective thymic and splenic products were already knôwn to differ in other functional systems, neuromuscular and immunological, in vitro and in vivo. The H-Y rejection response of young thymus-intact female mice was heightened by TP-5 and by SP-5. Neither TP-5 nor SP-5 affected the raised H-Y rejection response of splenectomized female mice. Whereas TP-5 lowered the raised H-Y rejection response of thymectomized female mice, as reported elsewhere, SP-5 did not. Thus, not only do these structurally very similar immunoregulators differ in their partcular functions, but the overall effect of these functions in vivo depends on the immune status of the recipient.