The MRL mouse has been shown to display unusual healing properties. In particular, when the ear pinna is hole punched, the hole that is made closes completely without scarring, with reformation of hair follicles and sebaceous glands, and regrowth of cartilage. Initial studies using (MRL/ lpr x C57BL/6) F(2) and backcross mice showed that this phenomenon is genetically determined and that multiple loci contribute to this quantitative trait. In the present study, with twice as many animals, we have confirmed many of the original heal loci and identified new ones. We have also found that this phenotype is sexually dimorphic in that female mice heal more quickly and more completely than male mice. To test the cause of this difference, we castrated both males and females. Castration of males led to better healing, although ovariectomy did not lead to worse healing in female mice. Finally, most heal loci were shown to be responsible for regulating healing primarily in male animals more than in females, or vice versa. Thus, sex plays a highly significant role in the closure of wounded tissue in this mammalian model of healing and regeneration.