Purpose: The aim of this study is to study the feasibility, safety, and physiological effects of pulse pressure variation (PPV)-guided fluid therapy in patients after cardiac surgery. Materials and methods: We conducted a pilot prospective before-and-after study during mandatory ventilation after cardiac surgery in a tertiary intensive care unit. We introduced a protocol to deliver a fluid bolus for a PPV = 13 for at least > 10 minutes during the intervention period. Results: We studied 45 control patients and 53 intervention patients. During the intervention period, clinicians administered a fluid bolus on 79 of the defined PPV trigger episodes. Median total fluid intake was similar between 2 groups during mandatory ventilation (1297 mL [interquartile range 549-1968] vs 1481 mL [807-2563]; P = .17) and the first 24 hours (3046 mL [interquartile range 2317-3982] vs 3017 mL [2192-4028]; P = .73). After adjusting for several baseline factors, PPV-guided fluid management significantly increased fluid intake during mandatory ventilation (P = .004) but not during the first 24 hours (P = .47). Pulse pressure variation-guided fluid therapy, however, did not significantly affect hemodynamic, renal, and metabolic variables. No serious adverse events were noted. Conclusions: Pulse pressure variation-guided fluid management was feasible and safe during mandatory ventilation after cardiac surgery. However, its advantages may be clinically small.