Plakortides are a subclass of marine endoperoxides with diverse biological activities. Their structural particularity derives from the C 4 and C 6 positions of the endoperoxide, substituted by ethyl groups. The ethyl plakortide Z has the simplest side chain among its congeners and is an excellent target for testing a universal strategy for the synthesis of this subfamily. Accordingly, we have synthesized for the first time a 6-membered member of the plakortides, using asymmetric Enders alkylation, regioselective cyclobutanol oxidative expansion, and peroxycarbenium ion-mediated diastereoselective C-C bond formation as key steps. Preparative HPLC separation of the various diastereoisomers obtained yielded a pure sample of synthetic ethyl plakortide Z, constituting the first total synthesis. Despite the lack of selectivity inherent in the synthesis of peroxide linkages involving radical reactions, the diastereomer separation step was offset by an efficient synthesis in just 11 steps and 4.2% overall yield.