3D-QSAR models for human TRPV1 channel antagonists were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), using a training set of 61 cinnamide TRPV1 antagonists and tested on an independent test set of 47 antagonists. Molecular alignment procedure included weights for both internal energy and atom-to-atom matching against a reference or probe. Sensitivity of results on partial charge assignments was explored using multiple charge sets. AM1-BCC charge assignments gave better results for both CoMFA and CoMSIA models. For the best CoMFA model, the statistics are, r2 = 0.96, q2 = 0.58, n = 61 for the training set and r2 = 0.50, n = 47 for the test set. For the best CoMSIA model, the statistics are r2 = 0.95, q2 = 0.57, n = 61 for the training set and r2 = 0.48, n = 47 for the test set. These models are consistent with the proposed binding modes and interactions of known activators of the TRPV1 channel such as capsaicin, in a structural model of the TM3/4 helical region of TRPV1.