The serum concentrations of receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) in age- and sex-matched groups of smokers and non-smokers with almost identical levels of periodontal disease were determined by an enzyme-linked immunosorbent assay (ELISA). We ensured that the 35 smokers were gender, age and clinically matched with a group of 35 non-smokers (confirmed by cotinine immunoassay) from the same population of maintained patients with susceptibility to periodontitis. Cigarette smoker patients tended to have lower serum concentrations of RANKL and OPG than non-smoker patients. While no statistically significant difference was observed for RANKL, there were significant differences in the median serum concentration of OPG (smokers 23.76 pM, non-smokers 59.28 pM) and the ratio of serum concentrations of RANKL and OPG. Concentrations of OPG in the smoker patients also had a statistically significant negative correlation with tobacco consumption. Bone loss in smoker-related periodontitis patients may be partially explained by suppression of OPG production.