Since it was previously shown that IFN, under certain conditions, can stimulate sensitization to SRBC, we examined the intensity and duration of DH to NDV in high and low IFN-alpha and -beta producing mice that carried either the h or I allele at the If-1 locus. In C57BL/6 mice (If-1h) DH to NDV is of higher intensity and longer duration than in BALB/c (If-1l). Evidence that this difference is related to the higher IFN-alpha and -beta production induced by NDV in C57BL/6 mice was obtained by comparing DH to NDV in C57BL/6 (If-1h) mice and in mice of three congenic strains, carrying the If-1l allele on a C57BL/6 background (B6.C-H-28c-If-1l). In the latter, DH to NDV was much more of BALB/c than of C57BL/6 type, since after footpad challenge a significant reaction was only observed at 24 hr and no longer at 48 hr. When the low endogenous IFN production of the If-1l congenic mice was compensated for by giving extra IFN-alpha and -beta a few hours after sensitization with NDV, DH was enhanced. If, on the other hand, anti IFN-alpha and -beta globulins were administered to either C57BL/6 or If-1l congenic mice immediately after sensitization with NDV, DH was decreased. These results indicate that, on a C57BL/6 background, the establishment of DH to NDV is influenced by the alleles at If-1, determining the levels of endogenous IFN-alpha and -beta induced by NDV.