Abstract Background and Aims A growing body of evidence have suggested hemodiafiltration (HDF) provide survival benefit for dialysis patients. HDF may improve immune modulation with enhanced clearance of azotemic toxins, compared to high-flux hemodialysis (HD). We therefore assess the effect of dialysis modalities on infection-related mortality in patients treated in real-world settings. Method We conducted a retrospective cohort-study based on 85,117 adult haemodialysis (HD) patients who were treated in EMEA NephroCare Clinics between January 1, 2019 and December 31, 2022. All patients’ data were extracted from the European Clinical Database (EuCliD®), including mortality from any infection, viral infection, and COVID-19 infection. The definition of mortality cause is based on ICD-10 codes. Any infection related mortality includes a broad range of infection disease types, such as viral, bacterial, parasitic, and fungal infections. The associations between dialysis modality and infection-related mortality were analyzed by multivariable Cox regression models, with both dialysis modality and COVID-19 infection as time-dependent covariates. To account for potential impact of difference in patients’ characteristics, we adjusted for multiple confounding factors. Competing risk analyses with death from non-infection as the competing event were performed by cause-specific and Fine-Gray subdistribution hazard models. Results At baseline 45.0% patients were treated with HDF, which changed to 52.6% by the end of follow-up. Of all HDF treatments in post-dilution mode (account for 98.4% HDF treatments) during follow-up, the average convection volume was 25.7 liters (median [interquartile range], 25.8 [23.9–28.0]). Patients treated with HDF at baseline were younger, with less comorbidities and longer dialysis vintage, compared to patients with HD (Table 1). During a median follow-up of 22.6 months, death from any infection occurred among 6.9% patients, of which 40.1% died from COVID-19 infection. Compared to HD, HDF was associated with a reduced risk of dying from any infection (hazard ratio [HR], 0.89 [95% CI, 0.82–0.97]), which however disappeared if excluding death from COVID-19 infection (Table 2). Similar pattern was also observed for death from viral infection. Association of HDF with death from COVID-19 infection persisted after controlling for multiple confounders (HR, 0.81 [95% CI, 0.71–0.93]). Similar results yielded from competing risk analyses. Conclusion In this large, unselected patient population, the beneficial effect of HDF for infection-related mortality was confined to mortality from COVID-19 infection. Further studies are needed to unravel the relation between dialysis modalities and death from different types of infection.