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The CXCR2 receptors play a pivotal role in inflammatory disorders and CXCR2 receptor antagonists can in principle be used in the treatment of inflammatory and related diseases. In this study, quantitative relationships between the structures of 130 antagonists of the CXCR2 receptors and their activities were investigated by the partial least squares (PLS) method. The genetic algorithm (GA) has been proposed for improvement of the performance of the PLS modeling by choosing the most relevant descriptors. The results of the factor analysis show that eight latent variables are able to describe about 86.77% of the variance in the experimental activity of the molecules in the training set. Power prediction of the QSAR models developed with SMLR, PLS and GA-PLS methods were evaluated using cross-validation, and validation through an external prediction set. The results showed satisfactory goodness-of-fit, robustness and perfect external predictive performance. A comparison between the different developed methods indicates that GA-PLS can be chosen as supreme model due to its better prediction ability than the other two methods. The applicability domain was used to define the area of reliable predictions. Furthermore, the in silico screening technique was applied to the proposed QSAR model and the structure and potency of new compounds were predicted. The developed models were found to be useful for the estimation of pIC50 of CXCR2 receptors for which no experimental data is available.