The safety of hydroxyethyl starches (HES) is still under debate. No studies have compared different dosing regimens of HES in cardiac surgery. We analyzed whether the incidence of Acute Kidney Injury (AKI) differed taking into account a weight-adjusted cumulative dose of HES 6% 130/0.4 for perioperative fluid therapy. This retrospective cohort study included all adult patients undergoing elective or emergency cardiac surgery with or without cardiopulmonary bypass. Exclusion criteria were patients on renal replacement therapy (RRT), cardiac trauma surgery, heart transplantation, patients with ventricular assist devices, subjects who required a surgical revision for bleeding and those whose medical records were incomplete. Primary endpoint was AKI following the creatinine based RIFLE classification. Secondary endpoints were 30-day mortality and RRT. Patients were divided into 2 groups whether they had received a cumulative HES dose of < 30 mL/kg (Low HES) or ≥ 30 mL/kg (High HES) during the intra- and postoperative period. A total of 1501 patients were analyzed with 983 patients in the Low HES and 518 subjects in the High HES group. 185 (18.8%) patients in the Low HES and 119 (23.0%) patients in the High HES group developed AKI (P = 0.06). In multivariable regression analysis the dose of HES administered per weight was not associated with AKI. After case-control matching 217 patients were analyzed in each group. AKI occurred in 39 (18.0%) patients in the Low HES and 50 (23.0%) patients in the High HES group (P = 0.19). In conditional regression analysis performed on the matched groups a lower weight-adjusted dose of HES was significantly associated with a reduced incidence of AKI [(Odds Ratio (95% CI) = 0.825 (0.727–0.936); P = 0.003]. In the absence of any safety study the cumulative dose of modern HES in cardiac surgery should be kept less than 30 mL/kg.