The potential use of air-gap membrane distillation (AGMD) process for the removal of copper sulfate (CuSO4) from aqueous solution was examined. A series of experiments were conducted to investigate the effects of both operation parameters and module parameters, including hot feed temperature(T3), coolant temperature (T1), feed flow rate (F), feed salt concentration (cf), vacuum pressure (P), the rate of hollow fiber membranes and heat-exchange hollow fibers (Nm/Nd) and the length of the modules (L) on permeate water flux (J), gained output ratio (GOR), water productivity (PV), and salt rejection rate (R) in AGMD process. It was found that the performance of AGMD process could be enhanced, but permeate water quality was deteriorated by adding vacuum pressure. Moreover, J declined, but PV and GOR increased as L increased. With the increment of Nm/Nd, J decreased when operation parameters keep constant, PV and GOR showed different variation trends with different T1 values due to the insufficient cold energy. The highest CuSO4 rejection rate exceeded 99.95%, so AGMD process has potential for CuSO4 separation from aqueous solution.