To identify the genetic factors affecting susceptibility to atherosclerosis, we studied the inheritance of plasma total cholesterol (TC) and HDL cholesterol (HDL-C) concentrations and susceptibility to atherosclerotic lesion formation in an (SM/J[SM] x NZB/B1NJ[NZB]) outcross, an (SM/NZB)FI[F1] x SM backcross, and the NXSM recombinant inbred (RI) strain set. After 18 or 26 weeks on the atherogenic diet, lesion sizes in female mice were 160+/-110 (SE) microm2 for NZB, 100+/-60 for F1, and 3800+/-920 for SM. After 0, 4, or 26 weeks on the atherogenic diet, NZB had higher TC and HDL-C levels than either SM or F1. The F1 progeny had TC and HDL-C levels slightly higher than or similar to the SM/J parent, while lesion size in the F1 progeny was more similar to the NZB parent. Among the 15 RI strains, 8 resembled NZB and F1, 3 resembled SM, and 4 were intermediate between NZB and SM for lesion size. For the (SM x NZB)F1 x SM backcross offspring, 26 resembled NZB and F1, 7 resembled SM, and 6 were intermediate between NZB and SM for lesion size. There was poor correlation between lesion size and plasma TC or HDL-C in the parental strains and the backcross. These data suggest that resistance to atherosclerosis is determined by at least one major dominant gene contributed by the NZB strain, which we have named Ath8. Ath8 segregates independently of genes controlling TC and HDL-C levels.