A series of mutations in mice was tested for splenic NK-cell activity against YAC-1 target cells. Mutations at six loci that reduce NK-cell activity in the homozygous state were identified, including beige (bg), hairless (hr), motheaten (me), obese (ob), steel (Sl) and, to lesser extent, dominant spotting (W). Motheaten mice displayed the most profound NK-cell deficiency, with NK-cell activity virtually absent. Two mutations, nude (nu) and lymphoproliferation (lpr), produced elevated NK-cell-mediated lysis. The double homozygous recessive nu/nu bg/bg nude-beige mouse was viable and NK-cell-deficient, with activity slightly higher than that of +/? bg/bg beige littermate controls. Pigmentation mutants related to beige, including pale ears (ep), pearl (pe) and ruby eyes (ru2J) did not dramatically influence NK-cell levels. Unlike the obese gene, other mutations leading to obesity, diabetes (db) and yellow (Ay), did not impair NK-cell function. The possible site of gene action of these mutations in the NK-cell pathway is discussed.