We present genetic analyses of murine weight loss during dietary restriction (DR) for females eating 60% ad libitum (AL). We examined five cohorts across 81 different strains (22 strains tested twice) that included the LXS and LSXSS recombinant inbred strains, the LXS parental strains ILS and ISS, and the classical inbreds 129S6, A, BALB/c, C57BL/6, C3H, and DBA. Weight loss exhibited highly significant genetic variation, with DR body weights ranging from ~60% to ~85% of AL body weight. This variation was not explained by the strain differences in absolute food intake, feces calorie content, motor activity, or AL body fat. Heritability was 40-50%, and several provisional quantitative trait loci were mapped. This variation can be used to test whether weight loss correlates with DR’s health benefits, independent of the reduction in calories. The genetic variation also implies the existence of genes that would be novel therapeutic targets, distinct from genes affecting AL body weight or body fat, for enhancing (or mitigating) weight loss during food restriction.