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Low nephron number has been recognised as an important cardiovascular risk factor and recently a strong correlation between renal mass and nephron number has been demonstrated in newborns. The aim of this study was to investigate individual, as well as combined, effects of common variants of genes which encode for major components of the renin–angiotensin system ( REN G10601A, AGT G(− 6)A, ACE I/D, AGTR1 A1166C) on kidney size in healthy, full-term newborns. A significant additive main effect of the ACE I/D polymorphism, as well as an additive-by-additive interaction between AGT G(− 6)A and AGTR1 A1166C variants, were found. The variance attributed to the epistatic effect was 27.9 ml 2 /m 4 , which accounted for 73.8% of the interaction variance (37.8 ml 2 /m 4 ), 66.4% of the genetic variance (42.0 ml 2 /m 4 ) and 4.4% to the total phenotypic variance (628 ml 2 /m 4 ). No other statistically significant main or epistatic effects were detected. Our results highlight the importance of considering gene–gene interactions as part of the genetic architecture of congenital nephron number, even when the loci do not show significant single locus effects. Unravelling the genetic determinants of low nephron number, along with early molecular screening, may well help to identify children at risk for cardiovascular disease. [ABSTRACT FROM AUTHOR]