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To examine the influence of genetic variations in heat shock proteins on trauma outcome.Prospective, noninterventional, single-center study.Level I trauma center.Eighty consecutive severe multiple trauma patients.None.Plasma concentrations of interleukin-6 and tumor necrosis factor-α were measured over a 5-day course by chemiluminescence-immunoassay. The genotypes of the polymorphisms HSPA1B (HSP70-2) G1538A and HSPA1L (HSP70-Hom) C2437T were determined by polymerase chain reaction and restriction cleavage with Pst I or Nco I, respectively. Allele frequency of the HSPA1B 1538 G allele was 0.569, and that of the HSPA1L 2437 T allele was 0.821. Interleukin-6 concentrations rapidly increased and dropped to almost normal after 5 days, whereas tumor necrosis factor-α concentrations increased until day 5. Patients carrying the genotypes HSPA1B AG or HSPA1L CT had significantly higher plasma concentrations of tumor necrosis factor-α and interleukin-6 compared with those with genotype GG or TT. Presence of the HSPA1L genotype CT also was a significant risk factor to develop liver failure (odds ratio, 4.6; 95% confidence interval, 1.5–14.1) and to acquire at least one complication severe enough to score three points according to the Denver multiple organ failure score (odds ratio, 3.0; 95% confidence interval, 1.1–9.2).The data indicate that genetic variations of the heat shock proteins HSPA1B and HSPA1L may contribute to clinical outcome after severe injury.