We studied sex differences in response to high K⁺ (HK) intake on thiazide-sensitive cation (Na⁺ and K⁺) excretion in wild-type (WT) and ANG II receptor subtype 1a (AT_1aR) knockout (KO) mice. Renal clearance experiments were performed to examine Na⁺-Cl⁻ cotransporter (NCC) activity on mice fed with control and HK (5% KCl, 7 days) diets. Hydrochlorothiazide (HCTZ)-induced changes in urine volume, glomerular filtration rate, absolute Na⁺ and K⁺ excretion, and fractional excretion were compared. HK-induced changes in NCC, Na⁺/H⁺ exchanger isoform 3 (NHE3), and ENaC expression were examined by Western blot analysis. In WT animals under the control diet, HCTZ-induced cation excretion was greater in female animals, reflecting larger increases in Na⁺ excretion, since there was little sex difference in HCTZ-induced K⁺ excretion. Under the HK diet, the sex difference in HCTZ-induced cation excretion was reduced because of larger increments in K⁺ excretion in male animals. The fraction of K⁺ excretion was 57 ± 5% in male WT animals and 36 ± 4% in female WT animals (P < 0.05), but this difference was absent in AT_1aR KO mice. NCC abundance was higher in female animals than in male animals but decreased by similar fractions on HK diet. NHE3 abundance decreased, whereas cleaved forms of γ-ENaC increased, with HK in all groups; these changes were similar in male and female animals and were not significantly affected by AT_1aR ablation. These results indicate that, with the HK diet, male animals display greater distal Na⁺ delivery and greater activation of K⁺ secretion mechanisms, all suggesting a more powerful male adaptation to HK intake.