Our aim was to determine whether thenar tissue oxygen saturation (S(tO2)), measured by noninvasive near-infrared spectroscopy, and its changes derived from an ischaemic challenge are associated with weaning outcome. Our study comprised a prospective observational study in a 26-bed medical-surgical intensive care unit. Patients receiving mechanical ventilation for >48 h, and considered ready to wean by their physicians underwent a 30-min weaning trial. S(tO2) was measured continuously on the thenar eminence. A transient vascular occlusion test was performed prior to and at the end of the 30-min weaning trial, in order to obtain S(tO2) deoxygenation and reoxygenation rates, and estimated local oxygen consumption. 37 patients were studied. Patients were classified as weaning success (n=24) or weaning failure (n=13). No significant demographic, respiratory or haemodynamic differences were observed between the groups at inclusion. Patients who failed the overall weaning process showed a significant increase in deoxygenation and in local oxygen consumption from baseline to 30 min of weaning trial, whereas no significant changes were observed in the weaning success group. Failure to wean from mechanical ventilation was associated with higher relative increases in deoxygenation after 30 min of spontaneous ventilation.