The objective of the present work was to investigate the effects of pH, ions, and excipients on the in vitro lipolysis of self-emulsifying drug delivery systems (SEDDS). Studies were performed in bio-relevant media using a pH stat autotitrator for analysis. The results demonstrated that alkaline media were essential for lipolysis, which was enhanced by divalent CaCl2 ions and medium chain glycerides. Monovalent NaCl and the hydrophile-lipophile balance (HLB) of the surfactant had insignificant effect on lipolysis. Consequently, it was concluded that the activity of lipase, at an optimum pH of 6.5, is the predominant factors for digestion of SEDDS.