Analysis of the immune system of spiny mice (Acomys cahirinus) has been limited. Originally grouped with Mus, Acomys has recently been placed closer to Meriones (gerbils). This study compared immunity in Acomys, Mus, and Meriones. Lymphocytes from all rodents examined proliferated in response to mitogen and superantigen stimulation. Only Mus T cells responded to anti-CD3 stimulation. Acomys, like Meriones, and Mus that express xid, did not respond to thymus-independent type 2 antigens. Flow cytometric analyses revealed that T cell-specific MAbs did not bind Acomys or Meriones lymphocytes. The B cell-specific anti-CD45R (B220) MAb detected all rodent B cells and revealed the absence of a CD45R(lo) subset in the peritoneal cavity of Acomys and Meriones. Bone marrow from Acomys and Meriones failed to reconstitute B cell function in SCID mice. Thus, in terms of immunity, Acomys appears to be more similar to Meriones than Mus.