A set of 40 phenothiazines, thioxanthenes, and structurally related drugs with multidrug resistance modulating activity in tumor cells in vitro were selected from literature data and subjected to three-dimensional quantitative structure-activity relationship study using comparative molecular field analysis (CoMFA). More than 350 CoMFA models were derived and evaluated using steric, electrostatic, and hydrophobic fields alone and in combination. Four alignment strategies based on selected atom pairs or field fit alignment were compared. Several training and test sets were analyzed for both neutral and protonated drug forms separately. Each chemical class was trained and tested individually, and finally the classes were combined together into integrated models. All models obtained were statistically significant and most of them highly predictive. All fields contributed to MDR reversing activity, and hydrophobic fields improved the correlative and predictive power of the models in all cases. The results point to the role of hydrophobicity as a space-directed molecular property to explain differences in anti-MDR activity of the drugs studied.