The p38-mitogen-activated protein kinases (p38-MAPKs) belong to a family of serine-threonine kinases activated by pro-inflammatory or stressful stimuli that are known to be involved in several diseases. Their biological importance, related to the release of inflammatory pro-cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), has generated many studies aiming at the development of selective inhibitors for the treatment of inflammatory diseases. In this work, we developed receptor-based three dimensional (3D) quantitative structure-activity relationship (QSAR) models for a series of 33 pyridinyl imidazole compounds [Liverton et al. (1999) 42:2180], using a methodology named free-energy force-field (FEFF) [Tokarski and Hopfinger (1997) 37:792], in which scaled intra- and intermolecular energy terms of the Assisted Model Building Energy Refinement (AMBER) force field combined with a hydration-shell solvation model are the independent variables used in the QSAR studies. Multiple temperature molecular-dynamics simulations (MDS) of ligand-protein complexes and genetic-function approximation (GFA) were employed using partial least squares (PLS) as the fitting functions to develop FEFF-3D-QSAR models for the binding process. The best model obtained in the FEFF-3D-QSAR receptor-dependent (RD) method shows the importance of the van der Waals energy change upon binding and the electrostatic energy in the interaction of ligands with the receptor. The QSAR equations described here show good predictability and may be regarded as representatives of the binding process of ligands to p38-MAPK. Additionally, we have compared the top FEFF-3D-QSAR model with receptor independent (RI) 4D-QSAR models developed in a recent study [Romeiro et al. (2005) 19:385].