Renal changes following hypophysectomy are investigated. Particular attention is given to sex differences in the ultrastructure of proximal tubule cells and in protein excretion. Regardless of gender, hypophysectomy is followed by an increase in urine volume. However, there is a concomitant reduction of proteinuria, which is much more pronounced in males than in females. Partial hypophysectomy with anterior pituitary function preserved also leads to increased urine excretion, but does not alter proteinuria. In both sexes there is a reduction of the tubule circumference, which again is more pronounced in males thereby moderating the sex difference. The proximal tubule cells display a segment- and sex-independent reduction in surface area, a decrease of Golgi areas and reduction of ribosomes. Mitochondrial changes (condensation of cristae) selectively affect the S3 segment. The changes in the lysosomes and microbodies are segment- and sex-dependent. The volume density of microbodies in the S3 segment increases considerably, particularly in females. The volume density of lysosomes undergoes an increase in the S1 cells of the males and a decrease in the S2 cells. In the females the volume density of these organelles shows little change in these tubule segments; a sex-dependent difference is not longer apparent in the S1 and S2 segments. By contrast, in S3, there is an increase in the volume density of lysosomes in both sexes. The present study confirms a connection between the morphology of lysosomes in the proximal tubule and proteinuria. The findings also point to a possible involvement of male sex hormones in the reabsorption of protein in the renal proximal tubule.