Physiological and immunological factors contributing to risk for upper respiratory symptoms (URS) in athletic populations remain under investigation. Single nucleotide changes (polymorphisms) in cytokine genes and alterations in associated gene expression may influence risk for URS in some athletes. The aim of this study was to compare the frequency of cytokine gene polymorphisms in athletes with or without a history of frequent URS. Cytokine gene polymorphisms were determined in samples from five previous investigations of immune function in highly-trained athletes (n=170). Participants were classified into two groups based on their self-reported number of episodes of URS in the preceding 12 months. Athletes were classified as healthy (n=82) if they reported < or =2 episodes of URS in the preceding 12 months. Athletes were classified as illness-prone (n=88) if reporting > or =3 episodes of URS. Polymorphisms in Interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4 and Interferon(IFN)-gamma were determined using real-time polymerase chain reaction allelic discrimination assays. The distribution of genotype frequencies between the two groups was compared using a Chi-square test and logistic regression was used to model risk for URS as a function of cytokine gene polymorphisms. There was a tendency for IL-6 (chi2 = 5.0, p = 0.08) and IL-4 (chi2 = 4.8, p = 0.09) genotype frequencies to differ between the groups. The IL-6 high-expression genotype was associated with an increased likelihood of > or =3 URS episodes in a 12 month period (odds ratio (OR): 2.87, 95% confidence interval (CI): 1.10-7.53; p = 0.03). The IL-2 high-expression genotype was associated with a tendency for a decreased likelihood of > or =3 URS episodes in a 12 month period (OR: 0.361, 95% CI: 0.124-1.06; p = 0.06). These data suggest cytokine gene polymorphisms may account in part for differences in risk for URS in highly-trained athletes.