The aim of the present study was (i) to investigate the relation between specific interleukin-1 (IL-1) gene polymorphisms and peri-implant bone loss at osseointegrated ITI(R) dental implants and (ii) to explore the association between these allelic variants of the IL-1 gene complex and peri-implant mucosal inflammation, in both smoking and non-smoking individuals. A sample of 90 consecutive Caucasian patients (aged 33-88 years), treated with at least one ITI-implant participated in this retrospective investigation. Standardized periapical radiographs were taken after prosthetic rehabilitation (133.6 days, SD 136.9 days) and at the time of the re-examination, on average 5.6 years (SD 2.5 years) thereafter. The radiographs were analyzed by a calibrated examiner for changes in peri-implant bone levels. The examiner was blind with respect to clinical parameters and IL-1 status. The distance between the implant shoulder and the first visible bone-implant contact (DIB) at the respective time points were measured using a computerized method. The absolute bone level difference during the years of service (ABL) and the annual bone loss (DeltaBL/year) were calculated for all the implants. Percentages of full mouth bleeding on probing (BOP), as well as of BOP calculated separately for teeth and implants, were determined for all visits and averaged for the entire observation period. Out of the total patient sample, there were 14 heavy smokers (= 20 cigarettes/day), 14 moderate smokers (5-19 cigarettes/day), 23 previous smokers (smoking cessation > 5 years) and 39 non-smokers. Twenty-eight (31.11%) patients were IL-1 genotype positive. Upon stratification for smoking status, significant differences were found for the variables ABL (P < 0.04, U-test) and DeltaBL/year (P < 0.04, U-test) between non-smokers and heavy smokers for the IL-1 genotype positive group but not for the IL-1 genotype negative group. Moreover, significant differences in ABL (P < 0.04, U-test) and DeltaBL/year (P < 0.04, U-test) were identified between former smokers and heavy smokers for the IL-1 genotype positive group. The differences in inflammatory parameters (BOP) did not reach statistical significance. This study suggests that in heavy cigarette smokers, carriage of a functionally significant IL-1 gene complex polymorphism is associated with an increased risk for peri-implant bone loss following prosthetic reconstruction and during the supportive periodontal care phase of the treatment.