Background: The objective of the present study was to seek out for novel 1, 3, 4-thiadiazole derivatives that would assure to become useful as histamine H3 receptor antagonist. A series of 2 piperidinopiperidine thiadiazole derivatives which were reported as histamine H3 receptor antagonist for the treatment of diabetes chosen for 3D-QSAR study in order to create a quantitative relationship between physiochemical properties and biological behavior of the compounds.Methods: 3D QSAR study by k nearest neighbor molecular field analysis (KNN MFA) method was performed on a series of thiadiazole derivatives as histamine h3 receptor inhibitors by the molecular design suites (VLifeMDS). This study was performed with 21 compounds (data set) using manual selection and random selection method for the splitting up of the data set into training and test set. KNN-MFA methodologies with SW (step wise) variable selection forward-backward, SA (Simulated Annealing) and GA (Genetic Algorithms) methods were used for building the QSAR models. Molecular structures of reported compounds were drawn in the 2 dimensional (2D) Draw app option in the tool menu of V Life MDS QSARPlus. Results: Model 1 was obtained by random selection method for test set and genetic algorithm as a variable selection method. It has been very good internal and the external predictive ability of ~70% and ~80% respectively. According to this model, the field grid points S_1208, E_37, and S_894 representing steric, electrostatic and steric fields respectively, which play a significant role in the determination of biological activity. S_1208 with its negative range (-9.7885 17.6729 2) and position away from indicates the need of more steric groups at R1. E_37 is near R1 and has a negative range (-3.7686 15.3928 2) which directs the need of the negatively ionizable group at this position. S_894 is located near terminal piperidine moiety and has a negative range (-9.6628 9.3234 2) thus signifying the need of a less bulky group for favorable biological activity. Conclusion: This model indicates that one electrostatic and two steric descriptors were involved. The KNN-MFA contour plots provided a further understanding of the relationship between structural features of substituted thiadiazole derivatives and their activities, which should be applicable to design newer potential H3 receptor inhibitors.