We hypothesized that the control of the poly(epsilon-caprolactone) (PCL) nanosphere sizes could be achieved by controlling the size of the primary emulsion droplets considering a combined effect of the ethanol volume fraction in the organic phase and the stirring rate of the primary emulsion. In this way, we prepared poly(epsilon-caprolactone) (PCL) nanospheres in order to evaluate the effect of those variables on the hydrodynamic diameters of the nanoparticles by a 32 factorial design. The size distribution curves considering intensity, volume and number of particles showed monomodal distributions for all formulations. The nanoparticle diameters (z-average) decreased from 423 to 249 nm with the increase in both the ethanol volume fraction from 0.0 to 0.4 and the stirring rate from 9500 to 17500 rpm. The polydispersity indexes ranged from 0.076 to 0.176. A statistical model based on the regression coefficients calculated by the factorial design analysis was proposed in order to predict the nanoparticle diameters. Using the predictive model, the results showed high similarity between the experimental and the predicted nanosphere diameters, validating the model for loaded PCL nanospheres. The backscattering profiles of the primary emulsions prepared using different proportions of ethyl acetate and ethanol showed a reduction in the size of the droplets from 1.659 microm to 0.706 microm with the increase in the ethanol volume fraction and the stirring rate. Ethanol decreased the restoring stress of the droplets as a consequence of the reduction in the interface tension. The decrease in the nanoparticle mean size was a consequence of the droplet size reduction in the primary emulsion.