P815 (H-2d) target cells incubated with synthetic peptides corresponding to region 170-182 of HLA or to region 141-161 of influenza nucleoprotein (NP) are lysed by DBA/2 derived cytolytic T cells (CTL) specific for HLA or by BALB/c derived CTL-specific for NP, respectively. Both peptide Ag are recognized in the context of Kd. We show herein that these unrelated, nonhomologous peptides clearly compete reciprocally for recognition by the appropriate Kd restricted CTL. In contrast, different NP peptides that are recognized by other CTL restricted by HLA-B37, H-2-Db or KK, either failed to compete or were much less efficient as competitors than NP peptides recognized in the context of Kd. The efficiency of a peptide as a competitor correlated with its potency as an Ag. The most efficient competitor was a variant peptide of NP 147-158 with R156 deleted, which had been previously shown to be 1,000 times more efficient as an Ag than its natural homolog. Our results suggest that peptides recognized by CTL in the context of the same MHC class I restriction element may bind to the same or interdependent site(s) on the restriction molecule.