Ca(2+)-Mg(2+)-ATPase is an important regulator of intracellular calcium concentration and therefore, of erythrocyte deformability. We have investigated the possible relationship between Ca(2+)-Mg(2+)-ATPase activity (ATPase) and ionized calcium (Ca(2+)), in diabetic patients with peripheral neuropathy. A total of 104 Type 2 diabetic patients (57 neuropathic and 47 non-neuropathic) and 25 non-diabetic subjects were studied. After an overnight fast, blood was taken for Ca(2+)-Mg(2+)-ATPase activity, Ca(2+), Mg(2+), PTH and HbA(1c). The neuropathy study group had significantly lower levels of ATPase, 6.6 (95% CI, 5.6-7.7) nmol/mg/min compared to controls 7. 1 (6.2-8.3) nmol/mg/min, P<0.001 and to diabetic patients without neuropathy 7.0 (6.0-8.1) nmol/mg/min, P<0.001. The study group had also lower levels of Ca(2+) (0.89+/-0.18 mmol/l vs. control 1.08+/-0. 24 mmol/l, P<0.01 and non-neuropathic 0.98+/-0.27 mmol/l, P<0.05) and Mg(2+) (0.73+/-0.13 mmol/l vs. control 0.81+/-0.14 mmol/l, P<0. 05), despite similar PTH levels. In diabetic subjects, no correlation was found between ATPase or Ca(2+) with glucose, HbA(1c), age or duration of diabetes. We conclude that in patients with diabetic neuropathy there are abnormalities of Ca(2+)-Mg(2+)-ATPase activity and Ca(2+). This provides further support for the role of microangiopathy in the pathogenesis of neuropathy.