Although diabetic retinopathy is a leading cause of blindness, the mechanisms underlying the disorder remain unresolved. Recent studies have reported both an increase in viscosity and a decrease in filterability of blood in diabetes, as well as increased activation of monocytes and granulocytes. These rheological effects have been implicated in capillary closure which is an early pathological change in diabetic retinopathy. The objective of this study was to quantitatively measure in vivo for the first time the resistance increase in capillary networks due to leukocyte-capillary plugging during experimental diabetes. Intravital measurements of plugging durations and frequencies were made throughout capillary networks in the spinotrapezius muscle of anesthetized rats subject to streptozotocin (STZ) induced hyperglycemia. These data were used to estimate the increase in microvascular flow resistance due to leukocyte plugging. The increase averaged 13.0% which is significantly different (p < 0.05) from the 1.1% observed in previous experiments with normal rats. Although the total white cell count was normal, the diabetic animals exhibited a significantly increased percentage of monocytes. A small but significant decrease in capillary diameter in the diabetic animals was also observed. Thus, leukocytes have a significant impact on microvascular hemodynamics in diabetic animals, and leukocyte-capillary plugging may be an important mechanism of capillary closure and subsequent microvascular dysfunction in diabetic retinopathy.