Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean ± SD 24- h urinary sodium was 197 ± 76.0 mmol (replete) and 67 ± 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 ± 11.3 μmol/kg · min (replete) and 37.0 ± 11.6 μmol/kg · min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 ± 21/78 ± 11 mmHg (replete) and 128 ± 12/73 ± 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.