Interleukin (IL)-1alpha, IL-1beta, and IL-1ra contribute to regulation of the inflammatory response in periodontal tissues. We aimed to investigate the distribution of polymorphisms in the IL-1 gene family among periodontitis patients and controls, taking into account smoking and microbiology as additional variables. Fifty-three non-smoking and 52 smoking patients with severe adult periodontitis and 53 controls were genotyped for bi-allelic IL-1A(-889), IL-1B(-3954), and a penta-allelic 86-bp VNTR IL-1RN gene polymorphisms. The presence of Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans was established by culture techniques. We found a higher frequency of allele 2 carriage in IL-1A, IL-1B, and IL-1RN in periodontitis patients who were non-smokers and in whom P. gingivalis and A. actinomycetemcomitans could not be detected (42.1% vs. 11.3% in controls; P = 0.0068; OR 5.7, 95% CI: 1.6-19.8). Our results provide evidence that polymorphisms in genes of the IL-1 family are associated with severe adult periodontitis in the absence of other risk factors tested in this patient population.