Objective: To investigate RANKL and OPG serum concentrations and the RANKL/OPG ratio in patients diagnosed with chronic periodontitis and attending dental school clinics in Makkah, Saudi Arabia. Methods : Patients seeking dental treatment at the Faculty of Dentistry Clinic, Umm Al Qura University were divided into periodontitis and control groups based on their clinical findings. Periodontitis was diagnosed in patients with a PD >4mm or CAL >3mm at more than 30% of the examined sites, and the radiographic evidence of alveolar bone loss was > 30% of teeth. RANKL and OPG serum concentrations (pg/ml) and RANKL/OPG ratio were determined. Results: Forty-three patients, including 32 females and 11 males with a mean age of 30 +/_ 8.48, were studied. Thirty patients were diagnosed with periodontitis, and 13 were in the control group. The patients with periodontitis had significantly higher RANKL (31.8 +/_ 27.5 vs. 18.7 +/_ 14.2 pg/ml, p=0.04) and OPG concentrations (58.0 +/_ 23.2 vs. 45.3 +/_ 10.0 pg/ml, p=0.03) than the control patients. The patients with periodontitis that smoked had significantly lower serum RANKL concentrations than those that did not smoke (37.8 +/_ 10.0 vs. 14.8 +/_ 10.0, p=0.0057 pg/ml). The RANKL/OPG serum ratio was higher in non-smokers than in smokers (0.6 vs. 0.3, p=0.017). The patients with generalized advanced periodontitis had significantly higher serum RANKL concentrations than those with the localized disease (56.8 +/_ 42.0 vs. 22.0 +/_ 12.8 pg/ml, p=0.03). Serum RANKL/OPG ratio was increased in patients with generalized disease (0.96 vs. 0.39, p=0.036). Serum RANKL/OPG ratio was also correlated with the amount of CAL (r = 0.459, p=0.04). Conclusions: Serum RANKL concentrations were increased in patients with periodontitis, in non-smokers, and in patients with the generalized advanced disease.