Lactate uptake by normoxic tissues is a pH-dependent phenomenon that occurs with increases in arterial lactate concentration. In this study we sought to determine the effect of hypoxia on lactate uptake by the rabbit hindlimb at different arterial blood pH (pHa). Two groups of rabbits were subjected to 20 min of arterial hypoxemia (PaO2 approximately 20 mm Hg). One group was allowed to maintain normal pHa (approximately 7.40 to 7.45; n = 5), whereas the other group was hyperventilated, resulting in hypocarbia and alkalemia (pHa > 7.50; n = 5). Lactate uptake was computed from measurements of femoral blood flow and the arterio-venous lactate difference. We found decreases in hindlimb O2 consumption during hypoxemia from 0.79 +/- 0.08 to 0.33 +/- 0.06 ml/min in the normal pH group (p < 0.01) and from 0.49 +/- 0.06 to 0.24 +/- 0.02 ml/min in the high pH group (p < 0.01). At that time there was net uptake of lactate by the hindlimb of the normal pH group (8.1 +/- 2.0 mumol/min; p < 0.001) and lactate release by the alkalemic group (1.61 +/- 1.0 mumol/min). Furthermore, hindlimb lactate uptake was associated with increased glucose consumption (p < 0.001). We hypothesize that the mechanisms responsible for lactate uptake by resting skeletal muscle during hypoxia may be similar to those that regulate lactate uptake during normoxic exercise.