First degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are often reported to be insulin resistant. To examine the possible role of reduced physical fitness in this condition 21 first degree relatives of NIDDM patients and 22 control subjects without any history of diabetes were examined employing a 150-min hyper-insulinaemic (0.6 mU insulin kg⁻¹ min⁻¹) euglycaemic clamp combined with the isotope dilution technique (3-³H-glucose, Hot GINF), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) and forearm glucose extraction were significantly diminished in the relatives (p < 0.01 and p < 0.05), but glucose oxidation and the suppressive effect on hepatic glucose production were normal. Arteriovenous differences across the forearm of the gluconeogenic precursors lactate, alanine and glycerol as well as the increments in forearm blood flow during hyperinsulinaemia were similar in the two groups. Maximal oxygen uptake (VO₂ max) was lower in the relatives than in the control subjects (36.8 ± 1.9 vs 42.1 ± 2.0 ml kg⁻¹ min⁻¹; p = 0.03). There was a highly significant correlation between Rd and VO₂ max in both relatives and control subjects (r = 0.68 and 0.66, respectively; both p < 0.001). Comparison of the linear regression analyses of insulin-stimulated Rd on VO₂ max in the two groups showed no significant differences between the slopes (0.10 ± 0.03 vs 0.09 ± 0.02) or the intercepts. In stepwise multiple linear regression analyses with insulinstimulated Rd as the dependent variable VO₂ max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. In conclusion, the insulin resistance in healthy first degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether, this finding is ascribable to environmental or genetic factors (e.g. differences in muscle fibre types, capillary density etc) remains to be determined.