Based on the concept of the individualized nature of sepsis, we investigated the significance of the -251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n = 146), community-acquired pneumonia (CAP, n = 109), intra-abdominal infections (IAI, n = 119), and primary bacteremia (BSI, n = 105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8.