E-cigarette use is dramatically increasing, particularly with adolescents. While the chemical composition of e-liquids and e-vapor is well characterized, the particle size distribution and the human airways deposition patterns of e-cigarette particles are understudied and poorly understood despite their likely contribution to adverse health effects from e-cigarette usage. In this study, we examined the impacts of e-cigarette device power, e-liquid composition, and vaping topography on e-cigarette particle sizes and their deposition in human airways. In addition, we observed that particle measurement conditions (dilution ratio, temperature, and humidity) significantly affect measured e-cigarette particle sizes. E-cigarette power output significantly increased particle count median diameters (CMD) from 174 ± 13 (particles generated under 6.4 W) to 236 ± 14 nm (particles generated under 31.1 W). E-cigarette particles generated from propylene glycol-based e-liquids (CMD = 145 ± 8 nm and mass median diameter [MMD] = 3.06 ± 0.17 μm) were smaller than those generated from vegetable glycerin-based e-liquids (CMD = 182 ± 9 nm and MMD = 3.37 ± 0.21 μm). Puff volume also impacted vapor particle size: CMD and MMD were 154 ± 11 nm and 3.50 ± 0.27 μm, 163 ± 6 nm and 3.35 ± 0.24 μm, and 146 ± 12 nm and 2.95 ± 0.14 μm, respectively, for 35, 90, and 170 mL puffs. Estimated e-cigarette particle mass deposition fractions in tracheobronchial and bronchoalveolar regions were 0.504-0.541 and 0.073-0.306, respectively. Interestingly, e-cigarette particles are smaller than the particles generated from cigarette smoking but have similar human airway deposition patterns.