Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), on a series of 43 hydroxyethylamine derivatives, acting as potent inhibitors of β-site amyloid precursor protein (APP) cleavage enzyme (BACE-1). The crystal structure of the BACE-1 enzyme (PDB ID: 2HM1) with one of the most active compound 28 was available, and we assumed it to be the bioactive conformation of the studied series, for 3D-QSAR analysis. Statistically significant 3D-QSAR model was established on a training set of 34 compounds, which were validated by a test set of 9 compounds. For the best CoMFA model, the statistics are, r2 = 0.998, r2cv =0.810, n = 34 for the training set and r2pred = 0.934, n = 9 for the test set. For the best CoMSIA model (combined steric, electrostatic, hydrophobic, and hydrogen bond donor fields), the statistics are r2 = 0.978, r2cv = 0.754, n = 34 for the training set and r2pred = 0.750, n = 9 for the test set. The resulting contour maps, produced by the best CoMFA and CoMSIA models, were used to identify the structural features relevant to the biological activity in this series of analogs. The data generated from the present study will further help to design novel, potent, and selective BACE-1 inhibitors.