Aim: The aim of the present explorative cross-sectional study was to evaluate the potential role of some periodontal variables in predicting sub-clinical atherosclerosis and systemic inflammation in young adults (=40 years) with severe periodontitis compared with healthy individuals without periodontitis. Materials and methods: A total of 90 systemically healthy subjects, 45 (mean age 36.35±3.65 years) affected by severe periodontitis (test group) and 45 individuals (mean age 33.78±3.28 years) without a history of periodontal disease (control group) were enrolled in the present study. Test and control groups were paired for age, gender, body mass index (BMI) and smoking habits. Carotid intima-media thickness (carotid IMT) was bilaterally assessed by ultrasonography at the level of the common carotid artery to evaluate sub-clinical atherosclerosis. Blood samples to assess inflammatory markers (leucocytes, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total serum cholesterol, high sensitivity C-reactive protein, glucose and haemoglobin A1c% were taken. Results: In periodontal patients, mean probing depth (PD) was a predictor of mean carotid IMT (P=0.0005), BMI (P=0.0002), systolic blood pressure (P=0.0300) and diastolic blood pressure (P= 0.0199). Full-mouth bleeding score (FMBS) was a predictor of C-reactive protein levels (P=0.0218). In controls, full-mouth plaque score was a predictor of glucose levels (P=0.0074) and higher FMBS of lower triglycerides levels (P=0.0312). Conclusion: Mean PD and FMBS may predict sub-clinical atherosclerosis and systemic inflammation in young adults with severe periodontitis.