The effect of biguanides on substrate metabolism of muscle was studied by measurement of arterial and deep venous concentrations of glucose, lactate pyruvate and oxygen and of forearm blood flow in 6 maturity onset diabetics before and after five days of oral phenformin (150 mg/day).At rest, substrate balances and forearm blood flow obtained before and after treatment with phenformin did not differ significantly. During work, before treatment, a considerable muscular release of glucose (-6.64 + 2.87 ~mol/100g -min), lactate and pyruvate developed, which decreased continuously during recovery. Treatment with phenformin revealed a significant net utilisation of glucose during work (1.66 + 1.87) and recovery (1.62 + 0.34). An almost identical quantity of lactate and pyruvate continued to be produced during work as before. However, during recovery, lactate release was increased (untreated: -1.42 _+ 0.67, treated: -2.96 _+ 1.08) while pyruvate release was reduced. Accordingly, while before treatment increased deep venous L/P ratio slowly normalized during recovery (12.7 _+ 2.3) it persisted after phenformin (29.7 _+ 9.5). Adaptation of muscular oxygen uptake during recovery occurred within 3 minutes before treatment (8.2 + 0.3), but not even within 5 minutes after treatment (10.8 _+ 0.5). Thus phenformin enhances muscle glucose uptake and lactate release. This peripheral effect may be of clinical importance, since an eightfold increase of muscle lactate and pyruvate release was found in one case of fatal, phenformin-induced lactic acidosis.