Renal histamine concentration, total histamine and protein contents were measured in rats made diabetic via iv streptozotocin injection and held for 13 weeks following diagnosis of diabetes. Insulin (7 U/day) or alpha-hydrazinohistidine (alpha-HH, 25 mg/kg/day) or both drugs were administered to diabetic subgroups the last 2 weeks of the holding period. Untreated diabetics developed significant increases of renal histamine concentration and total histamine content, up 45 and 46%, respectively. Drug interventions reduced the diabetic increases of histamine concentration and content (in order) as follows: diabetic-insulin, down 7 and 8%; diabetic-alpha-HH down 25 and 26%; diabetic-insulin + alpha-HH, down 35 and 36%. Renal tissue protein content was unchanged and qualitative proteinuria was present in all diabetic subgroups. The data indicate that in experimental diabetes there is an increase of the renal inducible histamine pool which is partially reduced by insulin and/or alpha-HH treatments. In view of the long-recognized actions of histamine upon microvascular permeability, elevated renal histamine may be one pathophysiological mediator of the diabetic functional renal microangiopathy manifest as proteinuria.