nowledge about simultaneous contributions of tissue microstructure and elastic properties on ultrasound speed in cortical bone is limited. In a previous study, porosities and elastic coefficients of cortical bone in human femurs were shown to change with age. In the present study, influences of inter-individual and site-dependent variation in cortical bone microstructure and elastic properties on radial speed of sound (SOS; at 4, 6, and 8 MHz) were investigated using three-dimensional (3D) finite difference time domain modeling. Models with fixed (nominal model) and sample-specific (sample-specific model) values of radial elastic coefficients were compared. Elastic coefficients and microstructure for samples (n = 24) of human femoral shafts (n = 6) were derived using scanning acoustic microscopy and micro-computed tomography images, respectively. Porosity-related SOS varied more extensively in nominal models than in sample-specific models. Linear correlation between pore separation and SOS was similar (R = 0.8, p < 0.01, for 4 MHz) for both models. The determination coefficient (R2 = 0.75, p < 0.05) between porosity and radial SOS, especially at 4 MHz, was highest in the posterior quadrant. The determination coefficient was lower for models with sample-specific values of radial elastic coefficient implemented (R2 < 0.33, p < 0.05), than for nominal models (0.48 < R2< 0.63, p < 0.05). This information could be useful in in vivo pulse-echo cortical thickness measurements applying constant SOS.