ABSTRACT: INTRODUCTION: Lactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication. METHODS: Multicentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93+/-0.20; lactate 18+/-6 mM at hospital admission) due to metformin (n=23) or phenformin (n=1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available. RESULTS: On day 1, VO2 was markedly depressed (67+/-28 ml/min/m2) despite a normal CI (3.4+/-1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0+/-1.0 ml O2/100 ml) or without (2.5+/-1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P<0.001, n=32). CONCLUSIONS: VO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia.