Study objective: The mini-fluid challenge may predict fluid responsiveness with minimum risk of fluid overloading. However, the amount of fluid as well as the best manner to evaluate the effect is unclear. In this prospective observational pilot study, the value of changes in pulse contour cardiac output (CO) measurements during mini-fluid challenges is investigated. Design: Prospective observational study. Setting: Intensive Care Unit of a university hospital. Patients: Twenty-one patients directly after elective cardiac surgery on mechanical ventilation. Interventions: The patients were subsequently given 10 intravenous boluses of 50 mL of hydroxyethyl starch with a total of 500 mL per patient while measuring pulse contour CO. Measurements: We measured CO by minimal invasive ModelflowR (COm) and PulseCOR (COli), before and one minute after each fluid bolus. We analyzed the smallest volume that was predictive of fluid responsiveness. A positive fluid response was defined as an increase in CO of > 10% after 500 mL fluid infusion. Main results: Fifteen patients (71%) were COm responders and 13 patients (62%) COli responders. An increase in COm after 150 mL of fluid > 5.0% yielded a positive and negative predictive value (+ PV and − PV) of 100% with an area under the curve (AUC) of 1.00 (P < 0.001). An increase in COli > 6.3% after 200 mL was able to predict a fluid response in COli after 500 mL with a + PV of 100% and − PV of 73%, with an AUC of 0.88 (P < 0.001). Conclusion: The use of minimal invasive ModelflowR pulse contour CO measurements following a mini-fluid challenge of 150 mL can predict fluid responsiveness and may help to improve fluid management.