Background Soluble inflammatory mediators are known to exacerbate sepsis-induced acute kidney injury (AKI). Continuous renal replacement therapy (CRRT) has been suggested to play a part in immunomodulation by cytokine removal. However, the effect of continuous venovenous hemodiafiltration (CVVHDF) dose on inflammatory cytokine removal and its influence on patient outcomes are not yet clear. Study Design Prospective, randomized, controlled, open-label trial. Setting & Participants Septic patients with AKI receiving CVVHDF for AKI. Intervention Conventional (40 mL/kg/h) and high (80 mL/kg/h) doses of CVVHDF for the duration of CRRT. Outcomes Patient and kidney survival at 28 and 90 days, circulating cytokine levels. Results 212 patients were randomly assigned into 2 groups. Mean age was 62.1 years, and 138 (65.1%) were men. Mean intervention durations were 5.4 and 6.2 days for the conventional- and high-dose groups, respectively. There were no differences in 28-day mortality (HR, 1.02; 95% CI, 0.73-1.43; P = 0.9) or 28-day kidney survival (HR, 0.96; 95% CI, 0.48-1.93; P = 0.9) between groups. High-dose CVVHDF, but not the conventional dose, significantly reduced interleukin 6 (IL-6), IL-8, IL-1b, and IL-10 levels. There were no differences in the development of electrolyte disturbances between the conventional- and high-dose groups. Limitations Small sample size. Only the predilution CVVHDF method was used and initiation criteria were not controlled. Conclusions High CVVHDF dose did not improve patient outcomes despite its significant influence on inflammatory cytokine removal. CRRT-induced immunomodulation may not be sufficient to influence clinical end points.