The aim of the present study was preparation of hyaluronan (HA) targeted solid lipid nanoparticles (SLNs) of etoposide. SLNs were prepared by an emulsification-solvent evaporation method and physically coated with HA. Four variables, including the ratio of cetyl alcohol to cationic lipid, cationic lipid type (stearylamine (SA) or dodecylamine (DDA)), lipid to HA ratio, and organic to aqueous phase ratio, were studied in an irregular fraction factorial design. Four responses, including particle size, zeta potential, drug loading, and 24-hour release efficiency percent, were measured for each formulation and then the optimization was carried out. The percent of HA coated on the SLNs was calculated by CHN elemental analysis which was shown to be about 55.89%. The cationic lipid type and the ratio of cetyl alcohol to cationic lipid had the highest influence on particle size and zeta potential, respectively. The highest effects of the ratio of lipid to HA and the organic to aqueous phase ratio were on the drug loading efficiency of SLNs. The optimized formulation of SLNs was obtained by SA, the equal proportion of cetyl alcohol and cationic lipid, the ratio of 1.5 for lipid to HA, and 10% of organic phase to aqueous phase.