Plasma histamine concentrations were measured in rats made diabetic via jugular vein injection of streptozotocin and held 4 weeks following diabetes diagnosis. At least 15 diabetic animals received insulin (6-8 U/day) or alpha-hydrazinohistidine (alpha-HH) for the last week of the holding period. alpha-HH is a specific inhibitor of histidine decarboxylase (HD), the principle histamine-forming enzyme in mammals. Plasma histamine concentrations, expressed as means and mean standard errors (ng/ml) were as follows: control, 25.5 +/- 2.4; diabetic, 47.1 +/- 5.2; diabetic-insulin, 34.6 +/- 2.9; diabetic-alpha-HH, 28.1 +/- 2.1. These data indicate that in experimental diabetes there is an expansion of the nascent, or inducible histamine pool, an increase which is reflected by increased circulating plasma histamine. This may be one component mediating altered microvessel as well as large vessel permeability characteristics, an underlying component of both diabetic microangiopathy and macroangiopathy.