We evaluated 2 strains of mice for their utility in the investigation of nutritional and molecular regulatory mechanisms of lactation. The lactational performance and milk composition were characterized for an inbred mouse strain, inbred Quackenbush Swiss line 5 (QSi5) selected persistently for fecundity, and a nonselected strain, CBA. The milk yield assessed by changes in BW in response to suckling of sustainable litter sizes for each strain was 3-fold greater (P < 0.001) in QSi5 mice than the CBA strain. The QSi5 mice also produced milk more efficiently (P < 0.001) than CBA mice, despite having the same quantity of mammary tissue per unit of BW. Milk composition did not vary between strains or by stage of lactation, with the exception of lactose concentration, which was greater (P = 0.003) in QSi5 mice. Expression of epsilon-casein was > or = 10-fold greater, and alpha(S1)-casein was > or = 3-fold greater, during mid and late lactation compared with early lactation in both strains, whereas kappa-casein underwent an apparent alteration in posttranslational modifications in both strains from early to mid lactation. Changes in casein composition coincided with an increased susceptibility to proteolytic degradation; hence milk from early lactation may be more readily degraded to facilitate digestion in the neonate. The greater milk synthetic capacity of QSi5 mice over the lactation cycle provides a useful model for studies of nutritional and molecular regulation of lactation.