The relationship between structural and hemodynamic heterogeneity of microvascular networks is examined by analyzing the effects of topological and geometric irregularities on network hemodynamics. Microscopic observations of a network in the rat mesentery provided data on length, diameter, and interconnection of all 913 segments. Two idealized network structures were derived from the observed network. In one, the topological structure was made symmetric; in another a further idealization was made by assigning equal lengths and diameters to all segments with topologically equivalent positions in the network. Blood flow through these three networks was simulated with a mathematical model based on experimental information on blood rheology. Overall network conductance and pressure distribution within the network were found to depend strongly on topological heterogeneity and less on geometric heterogeneity. In contrast, mean capillary hematocrit was sensitive to geometric heterogeneity but not to topological heterogeneity. Geometric and topological heterogeneity contributed equally to the dispersion of arteriovenous transit time. Hemodynamic characteristics of heterogeneous microvascular networks can only be adequately described if both topological and geometric variability in network structure are taken into account.