The influence of lipid composition and drug load on the in vitro performance of lipid-based drug delivery systems was investigated during dispersion and in vitro lipolysis of two self-nanoemulsifying drug delivery systems (SNEDDS). SNEDDS preconcentrates consisted of the same mass ratios of lipid, surfactant, and cosolvent but varied in the chain length of the lipid component. Utilization of the surfactant Cremophor EL resulted in pronounced changes in the droplet size of dispersed SNEDDS containing increasing drug loads of the poorly water-soluble compound simvastatin (SIM). In contrast, the droplet size of dispersed medium-chain (MC)-SNEDDS based on the surfactant Cremophor RH40 was not affected by increasing drug loads of SIM, whereas the droplet size of the corresponding long-chain (LC)-SNEDDS increased. During 60 min in vitro lipolysis, MC-SNEDDS maintained approximately 95% of SIM in solution, independent of the drug load. At the start of lipolysis of LC-SNEDDS, up to 34% of the drug precipitated. However, the initial precipitate dissolved in the lipolysis medium 30 min after start of in vitro lipolysis. The study suggests that drug load and lipid composition should be considered for the design of SNEDDS. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1721–1731, 2012