Background: Lung protective ventilation with low tidal volume (TV) and increased positive end-expiratory pressure (PEEP) can have unfavorable effects on the cardiovascular system. We aimed to investigate whether lung protective ventilation has adverse impact on hemodynamic, renal and hormonal variables. Methods: In this randomized, single-blinded, placebo-controlled study, 24 patients scheduled for robot-assisted radical prostatectomy were included. Patients were equally randomized to receive either ventilation with a TV of 6 ml/IBW and PEEP of 10 cm H2O (LTV-h.PEEP) or ventilation with a TV of 10 ml/IBW and PEEP of 4 cm H2O (HTV-l.PEEP). Before, during and after surgery, hemodynamic variables were measured, and blood and urine samples were collected. Blood samples were analyzed for plasma concentrations of electrolytes and vasoactive hormones. Urine samples were analyzed for excretions of electrolytes and markers of nephrotoxicity. Results: Comparable variables were found among the two groups, except for significantly higher postoperative levels of plasma brain natriuretic peptide (p = 0.033), albumin excretion (p = 0.012) and excretion of epithelial sodium channel (p = 0.045) in the LTV-h.PEEP ventilation group compared to the HTV-l.PEEP ventilation group. In the combined cohort, we found a significant decrease in creatinine clearance (112.0 [83.4;126.7] ml/min at baseline vs. 45.1 [25.4;84.3] ml/min during surgery) and a significant increase in plasma concentrations of renin, angiotensin II, and aldosterone. Conclusion: Lung protective ventilation was associated with minor adverse hemodynamic and renal effects postoperatively. All patients showed a substantial but transient reduction in renal function accompanied by activation of the renin-angiotensin-aldosterone system. Trial registration: ClinicalTrials, NCT02551341. Registered 13 September 2015.