A model is developed for predicting the resolution of interested component pair and calculating the optimum temperature programming condition in the comprehensive two-dimensional gas chromatography (GC × GC). Based on at least three isothermal runs, retention times and the peak widths at half-height on both dimensions are predicted for any kind of linear temperature-programmed run on the first dimension and isothermal runs on the second dimension. The calculation of the optimum temperature programming condition is based on the prediction of the resolution of “difficult-to-separate components” in a given mixture. The resolution of all the neighboring peaks on the first dimension is obtained by the predicted retention time and peak width on the first dimension, the resolution on the second dimension is calculated only for the adjacent components with un-enough resolution on the first dimension and eluted within a same modulation period on the second dimension. The optimum temperature programming condition is acquired when the resolutions of all components of interest by GC × GC separation meet the analytical requirement and the analysis time is the shortest. The validity of the model has been proven by using it to predict and optimize GC × GC temperature programming condition of an alkylpyridine mixture.