Background Extracorporeal circulation contributes to morbidity after open-heart surgery by causing a systemic inflammatory reaction. Modified ultrafiltration is a technique able to remove the fluid overload and inflammatory mediators associated with use of cardiopulmonary bypass. It has been shown to reduce morbidity after cardiac operations in children, but the impact on adult cardiac procedures is unknown. Methods and Results Five hundred seventy-three consecutive adult patients were prospectively randomized to either ultrafiltration after cardiopulmonary bypass (treatment) or to no ultrafiltration (control). Parsonnet score was used to assess the severity of the patients’ clinical conditions. Analysis was done with Student’s t test or Mann-Whitney U test for continuous variables and Fisher’s exact test or Pearson’s χ² for discrete variables. Hospital mortality was 2.5% (7 of 284) in the treatment group versus 3.8% (11 of 289) in the control group (P=0.357). Hospital morbidity was lower in treated patients (66 of 284 [23.2%] versus 117 of 289 [40.5%], P=0.0001). Cardiac morbidity was similar (26 of 284 [9.1%] versus 35 of 289 [12.1%], P=0.251), whereas significantly lower rates of respiratory (20 of 284 [7.0%] versus 36 of 289 [12.5%], P=0.029), neurological (5 of 284 [1.8%] versus 14 of 289 [4.8%], P=0.039), and gastrointestinal (0 of 284 versus 4 of 289 [1.4%], P=0.044) complications were found in treated patients. Transfusion requirements were also lower in treated patients (1.66±2.6 versus 2.25±3.8 U/patient, P=0.039). Duration of intensive care (39.9±49.2 versus 46.3±72.8 hours, P=0.218) and hospital stay (7.6±3.5 versus 7.9±4.4 days, P=0.372) were comparable. Conclusions Modified ultrafiltration after cardiopulmonary bypass is associated with a lower prevalence of early morbidity and lower blood transfusion requirements. The impact on length of hospital stay needs further analysis. Routine application of modified ultrafiltration after adult cardiac operations is warranted.