Three-dimensional quantitative structure activity relationship (3D-QSAR) study using comparative molecular field analysis (CoMFA) was performed on 2-(Substituted)-N-(5-aryl-1,3,4-thiadiazol-2-yl)acetamide derivatives for spontaneous motor activity. This study was performed using 42 compounds, in which the CoMFA model was developed using a training set of 36 compounds. Six compounds (selected randomly served as a test set), which were not used in model generation, were used to validate the CoMFA model. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2cv 0.889 and 0.714 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 83.3% and 16.7% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals) interactions. To visualize the CoMFA steric and electrostatic field from PLS analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity.