Leptin is strongly contributed to the clustering of metabolic syndrome (MetS) components and potentially can be regarded as a single predictor of MetS. This population-based study, for the first time, reports the diagnostic accuracy of different leptin cut-points for determining MetS. Further, the current study compares the predictive ability of the appropriate threshold of leptin with insulin resistance. Data of the individuals without history of known diabetes mellitus, aged 25-64 years, from the third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007) were analyzed. MetS was defined due to either adult treatment panel III (ATPIII) or the modified international diabetes federation (IDF) criteria. Receiver-operating characteristic (ROC) curves were depicted to define cut-off of serum leptin, using the maximum Youden index and the shortest distance methods. Further, the values of leptin cut-offs in prediction of MetS were compared with those of insulin resistance (defined as homeostasis model assessment of insulin resistance >1.775). In men, the optimal cut-offs of leptin for IDF- and ATPIII-defined MetS were 3.6 ng/ml (positive predictive value, PPV: 56.5%; negative predictive value, NPV: 72.7%) and 4.1 ng/ml (PPV: 49.6%; NPV: 78.1%), respectively. In women, the optimal threshold was equal to 11.0 ng/ml (PPV: 53.8%; NPV: 73.0% for IDF criteria and PPV: 60.1%; NPV: 64.9% for ATPIII criteria). The diagnostic accuracy of these values in identifying MetS was similar to that of insulin resistance. Therefore, leptin is comparable to insulin resistance in identifying MetS and can be used as single predictor of MetS.