The size dependent and size independent contributions to the mechanical properties of poly(ethyleneglycol) microspheres with encapsulated air, made for medical ultrasound imaging, have been studied. A relation between the size of microspheres in a reference group and their acoustic attenuation efficacy was derived by partial least square regression. The developed model was used to estimate acoustic attenuation as a function of the measured size distribution for various preparations made during formulation and process studies. The ratio between the measured attenuation and model estimated attenuation was then used to evaluate variations in the mechanical properties of the polymer shell and the contribution of such variations to the acoustical properties of the substance. The statistical parameter was compared with results for the mechanical compressibility derived from a theoretical approach and the results from the two methods mutually confirmed each other. The statistical procedure outlined has been found applicable for studies of other particulate products with size dependent in vitro or in vivo properties.