We have achieved the total synthesis of (-)-mniopetal E, a drimane sesquiterpenoid which inhibits the reverse transcriptase of human immunodeficiency virus (HIV)-1. Our enantiospecific total synthesis of this target molecule in naturally occurring form commenced with a known 2,3-anhydro-D-arabinitol derivative, which was prepared using the Sharpless asymmetric epoxidation strategy. The key steps of our total synthesis were as follows: (1) a combination of highly stereocontrolled inter- and intramolecular Horner-Emmons carbon elongations for construction of a butenolide tethering a 1,2,4, 9-functionalized nona-5,7-diene moiety at the beta-carbon, (2) stereoselective thermal intramolecular Diels-Alder reaction of the thus-formed trienic compound, providing preferentially an endo-cycloadduct with the desired pi-facial selection, and (3) efficient transformation of the gamma-lactone moiety in the major cycloadduct to the gamma-hydroxy-gamma-lactone part in mniopetal E. Our total synthesis of (-)-mniopetal E established the unsettled absolute stereochemistry of the antibiotic.