Regional 125I-albumin permeation and glomerular structural changes were assessed in male Sprague-Dawley rats with diabetes and/or hypertension. All rats underwent unilateral nephrectomy 2 weeks after induction of diabetes with streptozotocin. At the same time, one-half of the nondiabetic and diabetic animals were placed on 1% saline drinking water and given weekly intramuscular injections of deoxycorticosterone acetate to induce hypertension (systolic blood pressure greater than 150 mm Hg). Vascular permeability studies were performed after 1 and 3 months of hypertension. Hypertension, alone or in combination with diabetes, had no effect on weight gain, plasma glucose, or food consumption, but did increase 24-h urine volume in nondiabetics. In normotensive diabetics and in nondiabetic hypertensive rats, vascular 125I-albumin permeation was increased in eyes, aorta, and new granulation tissue (formed in a subcutaneous fabric implant), and glomerular basement membranes were thickened without any change in the fractional volume of the glomerulus occupied by mesangium. Urinary albumin and IgG excretion in nondiabetic hypertensive rats was increased much more than in normotensive diabetics. Hypertension and diabetes were additive in their effects on 125I-albumin permeation in eyes, aorta, and granulation tissue, and on glomerular basement membrane thickening, but were synergistic in their effects on urinary albumin excretion and mesangial fractional volume. The magnitude of the increase in vascular albumin permeation and urinary albumin and IgG excretion between and 1 and 3 months was much larger in diabetic hypertensive rats than in rats with hypertension or diabetes alone. Neither diabetes nor hypertension, alone or in combination, had any effect on albumin permeation in skeletal muscle, skin, heart, or brain. These findings demonstrate that hypertension and diabetes increase vascular albumin permeation in rats preferentially in tissues that correspond to sites of clinically significant vascular disease in human diabetics. They also attest to an important interaction between blood pressure-induced and diabetes-induced increases in vascular permeability in these tissues and in structural changes in the glomerular vasculature.