Surface effect responsible for some size-dependent characteristics can become distinctly important for piezoelectric nanomaterials with inherent large surface-to-volume ratio. In this paper, we investigate the surface effect on the free vibration behavior of a spherically isotropic piezoelectric nanosphere. Instead of directly using the well-known Huang-Yu surface piezoelectricity theory (HY theory), another general framework based on a thin shell layer model is proposed. A novel approach is developed to establish the surface piezoelectricity theory or the effective boundary conditions for piezoelectric nanospheres employing the state-space formalism. Three different sources of surface effect can be identified in the first-order surface piezoelectricity, i.e. the electroelastic effect, the inertia effect, and the thickness effect. It is found that the proposed theory becomes identical to the HY theory for a spherical material boundary if the transverse stress (TS) components are discarded and the electromechanical properties are properly defined. The nonaxisymmetric free vibration of a piezoelectric nanosphere with surface effect is then studied and an exact solution is obtained. In order to investigate the surface effect on the natural frequencies of piezoelectric nanospheres, numerical calculations are finally performed. Our numerical findings demonstrate that the surface effect, especially the thickness effect, may have a particularly significant influence on the free vibration of piezoelectric nanospheres. This work provides a more accurate prediction of the dynamic characteristics of piezoelectric nanospherical devices in Nano-Electro-Mechanical Systems (NEMS).