Calcium channel antagonists are among the most widely prescribed cardiovascular drugs. Their benefit is limited by the side effect of edema, the microvascular mechanism of which is not known. We compared the local effect on edema formation in rat skin and skeletal muscle of two calcium channel antagonists, diltiazem and verapamil, and determined if the edema effect correlated with changes in microvascular flow. An increase in microvascular flow can potentiate edema formation by increasing microvascular hydrostatic pressure and the proportion of the bed that is perfused. Diltiazem, but not verapamil or control, injected sc in scrotal skin caused plasma albumin leakage visualized as local bluing of tissue in rats that had been pretreated with Evans blue dye systemically. Topographic studies using Monastral blue dye showed that in the underlying cremaster muscle, diltiazem increased leakage of dye particles not from capillaries but from postcapillary venules. The postcapillary venule is associated with inflammatory edema, suggesting a direct effect of diltiazem on endothelial permeability. The local injection of diltiazem also increased significantly (P< 0.05) plasma leakage quantified as the local accumulation of systemically injected¹²⁵I-radiolabeled albumin, from 14.5 ± 2.0 and 6.9 ± 1.0 μl in control sites to 30.0 ± 7.3 and 18.0 ± 2.5 μl in dorsal skin and abdominal rat skin, respectively. In contrast, verapamil at similar doses did not increase plasma albumin leakage significantly. At the doses that caused local skin edema, diltiazem had less effect on microvascular skin blood flow, measured by a laser Doppler flow probe, (12.6 ± 5.3% at 15 min and 2.8 ± 8.4% change at 30 min) than verapamil (39.0 ± 7.3% at 15 min 30.0 ± 6.7% change at 30 min,P< 0.01). The microvascular effects of these two calcium channel antagonists differ in that diltiazem had a significant effect on microvascular permeability whereas verapamil had a significant effect on microvascular blood flow.