Abstract We have analysed the synthesis and phosphorylation of total cellular proteins and their modulation by sex steroids (testosterone and 17β-estradiol) in the brain cortex of adult (25–28 weeks) and old (54–58 weeks) male and female AKR mice. The level of ( 35S) methionine incorporation in total proteins is comparatively higher in males than females. It declines significantly in older males but shows no difference with age in females. After gonadectomy, the extent of ( 35S) methionine incorporation decreases in adults but not in the old. The incorporation is induced remarkably by estradiol in males and by both sex steroids in females. Further analysis by fluorography shows several proteins, but only a few (66, 45 and 29 kDa) vary in levels significantly with age, sex and hormonal treatment. The data on phosphorylation of total cellular proteins by ( 32P) orthophosphate incorporation exhibit no age-dependent variation. However, it is reduced drastically by gonadectomy in adults. After the addition of testosterone, the extent of phosphorylation is enhanced significantly in adults but remains the same in the old of both sexes. Estradiol also increases this modification remarkably in males of both ages and adult females, but shows no effect in old females. These results suggest that both testosterone and estradiol modulate the synthesis and phosphorylation of brain cortex proteins in age- and sex-dependent manner. This leads to alterations in physiological activities of the animal.