Raloxifene may confer vascular benefits without causing estrogen-related side effects. However, its action on renal vascular circulation is unknown. This study aimed to examine the sex difference and roles of endothelium and Ca²⁺ channels in the rat renovascular relaxation to raloxifene. On isolated intralobar renal artery rings mounted in a myograph and contracted by U46619, concentration-relaxation curves were constructed for raloxifene and contractions to CaCl₂ were studied. Changes in intracellular Ca²⁺ levels ([Ca²⁺]_i) of vascular smooth muscle (VSM) were measured by Fura-2 fluorescence. Raloxifene or 17-estradiol was equally effective in relaxing renal artery from both sexes with raloxifene being more potent than 17-estradiol. Endothelial denudation did not affect raloxifene-or 17-estradiol-induced relaxation. N^G-nitro-L-arginine methyl ester, charybdotoxin plus apamin, indomethacin, or ICI 182,780 did not modify the effect of raloxifene. Raloxifene caused similar relaxations in rings contracted by U46619 and high K⁺. Nifedipine attenuated the potency of raloxifene. Raloxifene reduced CaCl₂-induced contractions. 80 mM K⁺ stimulated an increase in VSM [Ca²⁺]_i and raloxifene attenuated this effect. Raloxifene-induced reduction in contraction and increase in VSM [Ca²⁺]_i was insensitive to ICI 182,780. In summary, raloxifene causes relaxation in rat renal arteries; this effect is independent of a functional endothelium and is not mediated by ICI 182,780-sensitive estrogen receptors. Raloxifene inhibited both contractions and VSM [Ca²⁺]_i in response to CaCl₂, indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca²⁺ influx via Ca²⁺ channels. There is little sex difference in raloxifene-induced relaxation.