Sex differences in varicose veins have been suggested; however, the venous mechanisms involved are unclear. We hypothesized sex differences in venous function, [Ca²⁺]_i and Ca²⁺-dependent mechanisms of venous contraction. Segments of inferior vena cava (IVC) from male and female rats were suspended between two hooks, labeled with fura-2, and placed in a spectrofluorometer for simultaneous measurement of contraction and [Ca²⁺]_i). In male IVC, phenylephrine (PHE, 10^-5 M) caused significant increase in contraction and [Ca²⁺]_i. In female IVC, PHE-induced contraction was significantly reduced, but [Ca²⁺]_i did not differ from males. Membrane depolarization by KCl (96 mM), which stimulates Ca²⁺ influx, caused parallel increases in contraction and [Ca²⁺]_i in male IVC, and the KCl-induced contraction was significantly reduced in parallel with [Ca²⁺]_i in female IVC. In male IVC stimulated with 0 Ca²⁺ KCl solution, the addition of extracellular Ca²⁺ ([Ca²⁺]_e) (0.1, 0.3, 0.6, 1 and 2.5 mM) caused stepwise increases in contraction and [Ca²⁺]_i, and both the KCl-induced [Ca²⁺]_e-contraction curve and the [Ca²⁺]_e-[Ca²⁺]_i curve were reduced in female IVC, suggesting reduced Ca²⁺ entry via voltage-gated channels. The PHE-induced [Ca²⁺]_e-contraction curve was significantly reduced in females, but the [Ca²⁺]_e-[Ca²⁺]_i curve was similar in female and male IVC, suggesting the involvement of other mechanisms in addition to Ca²⁺ entry. The [Ca²⁺]_e-contraction and [Ca²⁺]_e-[Ca²⁺]_i curves were used to construct the [Ca²⁺]_i-contraction relationship. The KCl-induced [Ca²⁺]_i-contraction relationship was superimposed in male and female IVC. In contrast, the PHE-induced [Ca²⁺]_i-contraction relationship was reduced and located to the right in female compared with male IVC, suggesting reduced [Ca²⁺]_i sensitivity of the venous contractile myofilaments. The reduced contraction, [Ca²⁺]_i, and [Ca²⁺]_i sensitivity in female veins render them more prone to dilation. These sex-specific reductions in venous function, if also occur in human veins, may play a role in the greater incidence of varicose veins in females.