Background: Olmesartan medoxomil is an angiotensin II receptor blocker antihypertensive drug which has low oral bioavailability because of poor aqueous solubility. Objective: The objective of present research is development and optimization of Olmesartan medoxomil loaded self-microemulsifying drug delivery system by D-optimal mixture design to improve its dissolution rate. Methods: Solubility of Olmesartan medoxomil was determined in different oils, surfactants and co-surfactants. Pseudo ternary diagram was constructed for identification of self-microemulsification region. The D-optimal mixture design was employed for optimization of SMEDDS formulations wherein the factors optimized were the concentration of oil (X1), surfactant (X2) and co-surfactant (X3) and the response were globule size (Y1) and dissolution rate (Y2). Developed self-microemulsifying drug delivery system were further assessed for self-emulsification time, drug loading capacity, transparency, globule size, in vitro dissolution and comparative in vitro dissolution testing of optimized formulation with pure medicament and commercially available product. Results: The application of D-optimal mixture design resulted in 14 batches out of which F-5 was found to be the optimized batch which contained Olmesartan medoxomil (20 mg), Capmul MCM EP (23% v/v), Kolliphore EL (49% v/v) and Transcutol P (28% v/v) having globule size of 105 nm, 94.7% dissolution within 30 minutes. In vitro dissolution rate of the drug from SMEDDS was appreciably higher than that of pure drug and marketed product. Conclusion: Olmesartan medoxomil self-microemulsifying drug delivery system was successfully developed and this approach could prove to be suitable for improvement of dissolution rate of BCS II class drugs.