Background Body fat distribution influences the risk of cardio-metabolic disease in people with overweight. This study was aimed at identifying the anthropometric parameters more strongly associated with the majority of cardio-metabolic risk factors. Methods This study included 1214 subjects (840 women), with a body-mass-index (BMI) ≥ 25 Kg/m2, aged 39.2 ± 13 years. Fasting blood glucose (FBG), triglycerides (TG), total, HDL- and LDL-cholesterol, uric acid, vitamin D, high-sensitive C-reactive protein (hs-CRP), white blood cells (WBC), platelets, insulin and insulin resistance (HOMA-IR), systolic (SBP) and diastolic blood pressure (DBP), smoking habit and snoring were evaluated as cardio-metabolic risk factors.We also included the Systematic COronary Risk Evaluation (SCORE) to estimate cardiovascular risk in our study population. BMI, waist circumference (WC), waist-to-height-ratio (WHtR) and neck circumference (NC) were evaluated as anthropometric parameters. Results All four anthropometric parameters were positively associated to SBP, DBP, TG, FBG, insulin, HOMA-IR, WBC, and snoring (p<0.001), and negatively associated with HDL-cholesterol (p<0.001). NC showed a positive association with LDL-cholesterol (β = 0.76; p = 0.01; 95% C.I. 0.19 to 1.32), while vitamin D was negatively associated to WC (β = -0.16; p<0.001; 95% C.I. -0.24 to -0.09), BMI (β = 0.42); p<0.001; 95% C.I. -0.56 to -0.28) and WHtR (β = -24.46; p<0.001; 95% C.I. -37 to -11.9). Hs-CRP was positively correlated with WC (β = 0.003; p = 0.003; 95% C.I. 0.001 to 0.006), BMI (β = 0.01; p = 0.02; 95% C.I. 0.001 to 0.012) and WHtR (β = 0.55; p = 0.01; 95% C.I. 0.14 to 0.96). SCORE was associated to NC (β = 0.15; 95% CI 0.12 to 0.18; p<0.001), BMI (β = -0.18; 95% CI -0.22 to 0.14; p<0.001) and WHtR (β = 7.56; 95% CI 5.30 to 9.82; p<0.001). Conclusions NC, combined with BMI and WC or WHtR could represent an essential tool for use in clinical practice to define the cardio-metabolic risk in individuals with excess body weight.