We report a total synthesis of tiacumicin B, one of the most structurally complex natural antibiotic macrolides. Endowed with remarkable biological properties, it is used to treat very severe intestinal infections. The strategy is in part based on our experience of the synthesis of the tiacumicin B aglycone, and on the decisive implementation of an H-bond-mediated Aglycone Delivery (HAD) using sulfoxides as anomeric leaving-groups. This new HAD variant permitted highly beta-selective rhamnosylation and noviosylation. To increase the convergence, the rhamnosylated C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting the reliable Suzuki-Miyaura cross-coupling conditions used for the aglycone synthesis. The ring-size selective macrolactonization provided a compound engaged directly in the noviolysation step with a virtually total beta-selectivity. The final and efficient removal of all the protective groups (PGs) provided synthetic tiacumicin B.