Oleoyl-diethanolamide was synthesized through amidification of diethanolamine (DEA) with oleic acid (OA) using immobile lipase as a biocatalyst. Response Surface Methodology (RSM) based on five-level five variable, Central Composite Rotatable Design (CCRD) was developed to study and to optimize the reaction conditions of oleoyl-diethanolamide synthesis under solvent-free system. The influence of the five main variables namely temperature, reaction time, enzyme amount, substrate molar ratio and step of amine added on amide synthesized was analyzed. Results concluded that quadratic polynomial models is in accordance with the data obtained, with the value of R² is 0.9846. Although the effect of the gradual addition of the amine is not so significant, but it minimize problems of formation of ion pairs amine/fatty acid highly viscous. Oleic acid converted is 61.35% obtained at the optimum conditions 70^oC, 24h, enzyme amount 12% (wt/wtOA), three step of amine added and the DEA/OA molar ratio of 7. This is a high ratio of substrate because amine served as a solvent in the reaction. The identity of the oleoyl diethanolamide was confirmed by FTIR. Solvent-free conditions can be used even oleic acid is converted less (61.35%) than synthesis using a solvent (78%).