In a vascular network blood flow rate is proportional to the arteriovenous pressure difference and inversely proportional to the viscous and geometric resistances. The geometric resistance to tumor blood flow was determined by perfusing tissue-isolated mammary adenocarcinoma (R3230AC; N = 40; tumor weight, 1.8 +/- 1.2 (SD) g; range, 0.5-6.6 g) ex vivo with an acellular Krebs-Henseleit medium (viscosity, 0.9 g/m/s) at rates of 0.1 to 60 ml/h and arteriovenous pressure differences of 0 to 120 mm Hg. Below perfusion pressures of 40 mm Hg, pressure-flow behavior was always nonlinear, indicating elevated geometric resistance and a reduction in vascular cross-sectional area with decreasing microvessel pressure. However, above 40 mm Hg, pressure-flow behavior was linear demonstrating a constant geometric resistance, z0 and a constant vascular cross-sectional area for flow. z0 increased linearly from 1.6 to 17.3 X 10(8) g/cm3 as tumor weight increased from 0.5 to 6.6 g. This dependence of z0 upon tumor size is in agreement with the decrease in tumor perfusion rates with tumor growth observed in vivo. Comparison with previous studies of normal organs and tissues shows that z0 in tumors can be as much as 1-2 orders of magnitude higher, depending upon tumor weight. This dependence of geometric resistance on perfusion pressure and tumor size offers novel insights into the dynamics of tumor microcirculation and has significant clinical implications.