The global inhomogeneity (GI) index is a parameter of ventilation inhomogeneity that can be calculated from images of tidal ventilation distribution obtained by electrical impedance tomography (EIT). It has been suggested that the GI index may be useful for individual adjustment of positive end-expiratory pressure (PEEP) and for guidance of ventilator therapy. The aim of the present work was to assess the influence of tidal volume (VT) on the GI index values. EIT data from 9 patients with acute respiratory distress syndrome ventilated with a low and a high VT of 5 ± 1 (mean ± SD) and 9 ± 1 ml kg(-1) predicted body weight at a high and a low level of PEEP (PEEPhigh, PEEPlow) were analyzed. PEEPhigh and PEEPlow were set 2 cmH2O above and 5 cmH2O below the lower inflection point of a quasi-static pressure volume loop, respectively. The lower inflection point was identified at 8.1 ± 1.4 (mean ± SD) cmH2O, resulting in a PEEPhigh of 10.1 ± 1.4 and a PEEPlow of 3.1 ± 1.4 cmH2O. At PEEPhigh, we found no significant trend in GI index with low VT when compared to high VT (0.49 ± 0.15 versus 0.44 ± 0.09, p = 0.13). At PEEPlow, we found a significantly higher GI index with low VT compared to high VT (0.66 ± 0.19 versus 0.59 ± 0.17, p = 0.01). When comparing the PEEP levels, we found a significantly lower GI index at PEEPhigh both for high and low VT. We conclude that high VT may lead to a lower GI index, especially at low PEEP settings. This should be taken into account when using the GI index for individual adjustment of ventilator settings.