To study the effects of a specific glucagon receptor antagonist (Bay 27–9955), on plasma glucose concentrations and rates of glucose production in response to hyperglucagonaemia in humans. The study was conducted as a two-dose [Low Dose Bay 27–9955 70 mg, (n = 6), High Dose Bay 27–9955 200 mg, (n = 8)], double blind, placebo controlled, crossover study. Basal glucose production was measured after an overnight fast with [6,6-2H]. At 0 min Bay 27–9955 or placebo was administeredand at 120 min an infusion of somatostatin [0.1 μg · (kg · min)–1], insulin [24 pmol · (m2· min)–1] and glucagon [3 ng · (kg · min)–1] was initiated. Basal plasma glucose concentrations were about 5 mmol/l and basal rates of glucose production were about 13 μmol · (kg · min)–1. During the hyperglucagonaemic period, plasma glucagon concentrations doubled to 100 pg/ml, plasma glucose concentration increased by 75 % to a peak of about 10 mmol/l and glucose production doubled to about 23 μmol · (kg · min)–1 (p < 0.0001 vs basal). In the High Dose Group these effects of glucagon were markedly blunted, plasma glucose concentrations were 7.6 ± 1.1 mmol/l (p = 0.012 vs placebo) and rates of glucose production increased minimally to 15.3 ± 1.9 μmol · (kg-min)–1 (p < 0.0003 vs placebo]. In the Low Dose Group, there was a proportional decrease in the effects of Bay 27–9955 on these parameters. Bay 27–9955 is an effective and safe glucagon antagonist in humans. Given the potentially important role of glucagon in increasing glucose production and gluconeogenesis in patients with Type II (non-insulin-dependent) diabetes mellitus this agent could represent an innovative class of therapeutic agents for the disease. [Diabetologia (2001) 44: 2018–2024]