In Europe there is considerable variation in mortality on renal replacement therapy (RRT). The causes of this variation are still poorly understood. We hypothesized that differences in mortality in the general population contribute to differences in mortality on RRT. To evaluate this relationship, we studied general population statistics obtained from Eurostat and the individual data of 67,692 patients on RRT from 15 national and regional renal registries. These 15 registries were divided into two geographical regions: North and South Europe. Cox regression was used to assess the relative risk of death (RR) for each region with adjustment for age, gender, diabetes, and additionally general population mortality. In patients on RRT the age, gender and diabetes adjusted RR of death was 0.65 (95% CI (0.64-0.66)) for South compared to North, while in the general population the age and gender standardized RR of death was 0.91. After adjustment for general population mortality in addition to age, gender, and diabetes, the RR of death for patients on RRT in the South changed from 0.65 to 0.74 (95% CI (0.72-0.75)), which indicates that general population mortality accounted for 26% of the region-related mortality difference on RRT. In conclusion, within Europe there exist considerable international differences in the mortality of patients on RRT. Twenty-six percent of the European north-south mortality difference in RRT could be attributed to differences in general population mortality. Our data support the hypothesis that general population mortality is an important factor to take into account when making RRT mortality comparisons.