Lymphocytes represent a potentially important proinflammatory cell that localizes to atherosclerotic lesions. To determine whether they contribute to lesion development, atherosclerosis-prone (LDLR(-/-)) mice were crossed with lymphocyte-deficient (RAG1(-/-)) mice to generate double knockout progeny. After 8 weeks on a Western-type diet (WTD), lesion development was reduced by 54% in double knockout mice, as compared with matched LDLR(-/-) controls. However, these significant differences in lesion area gradually subsided as the WTD was continued for 12 and 16 weeks. Consistent with this observation, histological studies determined that lesion initiation and early progression were delayed in RAG1/LDL-R double knockout mice. Differences in lesion area did not correlate with any significant alterations in plasma lipid levels. These studies suggest that lymphocytes play an important role early in atherogenesis.