There is no agreement on gold standard method for positive end-expiratory pressure (PEEP) titration. Electrical impedance tomography (EIT) may aid in finding the optimal PEEP level. In this pilot trial, we investigated potential differences in the suggested optimal PEEP (BestPEEP) as derived by respiratory compliance and EIT-derived parameters. We examined if compliance-derived PEEP differs with regard to the regional ventilation distribution in relation to atelectasis and hyperinflation. Measurements were performed during an incremental/decremental PEEP trial in 15 ventilated intensive care patients suffering from mild-to-moderate impairment of oxygenation due to sepsis, pneumonia, trauma and metabolic and ischemic disorders. Measurement agreement was analyzed using Bland-Altman plots. We observed a diversity of EIT-derived and compliance-based optimal PEEP in the evaluated patients. BestPEEPCompliance did not necessarily correspond to the BestPEEPODCL with the least regional overdistension and collapse. The collapsed area was significantly smaller when the overdistension/collapse index was used for PEEP definition (p=0.022). Our results showed a clinically relevant difference in the suggested optimal PEEP levels when using different parameters for PEEP titration. The compliance-derived PEEP level revealed a higher proportion of residual regional atelectasis as compared to EIT-based PEEP.