To determine whether thenar tissue oxygen saturation (StO2) measured by non-invasive near-infrared spectroscopy, and its changes derived from an ischemic challenge, are associated to weaning outcome. Prospective observational study in a 26-bed medical-surgical intensive care unit. Patients receiving mechanical ventilation (MV) for >48 hours, and considered ready to wean by their physicians, underwent a 30-minute weaning trial (WT). StO2 was measured continuously on the thenar eminence. A transient vascular occlusion test (VOT) was performed prior to and 30 minutes into the WT, in order to obtain StO2 deoxygenation (DeO2) and reoxygenation rates, and estimated local oxygen consumption (nirVO2). Thirty-seven patients were studied. Patients were classified as weaning success (n=24) or weaning failure (n=13). No significant demographic, respiratory or hemodynamic differences were observed between both groups at inclusion. Patients who failed the overall weaning process showed a significant increase in DeO2 and in nirVO2 from baseline to 30 min of WT, whereas no significant changes were observed in the weaning success group. Failure to wean from mechanical ventilation was associated to higher relative increases in DeO2 after 30 minutes of spontaneous ventilation.