The use of CE coupled with MS (CE-MS) has evolved as a useful tool to analyze charged species in small sample volumes. Because of its sensitivity, versatility and ease of implementation, the ESI interface is currently the method of choice to hyphenate CE to MS. An alternative can be the atmospheric pressure photoionization (APPI) source, however, numerous parameters must be optimized for its coupling to CE. After evaluation of the sheath liquid composition and the CE capillary outlet position, an experimental design methodology was assessed for optimizing other ionization source parameters, such as sheath liquid flow rate, drying gas flow rate and temperature, nebulizing gas pressure, vaporizer temperature, and capillary voltage. For this purpose, a fractional factorial design (FFD) was selected as a screening procedure to identify factors which significantly influence sensitivity and efficiency. A face-centered central composite design (CCD) was then used to predict and optimize sensitivity, taking into account the most relevant variables. Sensitivity was finally evaluated with the optimized conditions and height-to-noise ratios (H/N) around 10 were achieved for an injection of 200 ng/mL of each analyte.