An efficient stereoselective total synthesis of (+)-mupirocin H is described. The chiron and asymmetric strategies were appropriately utilized for the rapid construction of the novel five-membered lactone with six stereogenic centres. The C3–C5 triol segment was derived directly from readily-available D-ribose, and the chirality at the C6 position was introduced by means of substrate-controlled conjugate addition. The remaining chiral centers (C10 and C11) were obtained by Oppolzer's protocol, and the olefin was generated through a Julia–Kocienski olefination.