The lpr gene has recently been shown to encode a functional mutation in the Fas receptor, a molecule involved in transducing apoptotic signals. Mice homozygous for the lpr gene develop an autoimmune syndrome accompanied by massive accumulation of double‐negative (DN) CD4⁻8⁻B220⁺ T cell receptor‐α/β⁺ cells. In order to investigate the origin of these DN T cells, we derived lpr/lpr mice lacking major histocompatibility complex (MHC) class I molecules by intercrossing them with β2‐microglobulin (β2m)‐deficient mice. Interestingly, these lprβ2m–/– mice develop 13‐fold fewer DN T cells in lymph nodes as compared to lpr/lpr wild‐type (lprWT) mice. Analysis of anti‐DNA antibodies and rheumatoid factor in serum demonstrates that lprβ2m–/– mice produce comparable levels of autoantibodies to lprWT mice. Collectively our data indicate that MHC class I molecules control the development of DN T cells but not autoantibody production in Ipr/lpr mice and support the hypothesis that the majority of DN T cells may be derived from cells of the CD8 lineage.