Chronic low-grade elevations in circulating levels of interleukin (IL)-6 act as a marker of subclinical cardiovascular diseases (CVD) and provide an independent predictor of increased mortality in elderly populations. The purpose of the present study was to test the hypothesis that the IL-6 -174G>C promoter polymorphism was associated with a high prevalence of CVD and acted as an independent predictor of mortality in a longitudinal study of 324 relatively healthy 80-year-old people with a history of CVD in 18% of the cases. The C allele was associated with elevated serum levels of IL-6 at baseline and the CC genotype had a high prevalence of CVD. A Cox regression model was used to explore the effect of the polymorphism on survival in the following six years. A significant interaction was found between smoking status and the polymorphism. Thus, C allele carrier status was associated with increased all-cause mortality risk in non-smokers independently of sex, body mass index, co-morbidity, and low-grade elevations in serum levels of IL-6. This effect was not detected among smokers. We conclude that the IL-6 -174G>C polymorphism was an independent predictor of all-cause mortality in octogenarians but the effect was complex and interacted with the smoking status.