Activins, integral members of the transforming growth factor -β superfamily, are negative regulators of muscle growth. Elevated levels of activins in patients diagnosed with metastatic cancers are associated with marked body wasting, termed cancer-cachexia. Significantly, cachexia is observed in the majority of patients suffering advanced cancers and accountable for 25% of cancer-related mortalities. The favoured approach to combat activin hyperactivity in models of cancer-cachexia uses soluble forms of the activin type II receptors (sActRIIA/B). By binding to diverse TGF-β proteins, sActRIIA/B can increase muscle and bone mass, correct anaemia or protect against diet-induced obesity. While exciting, these multiple actions of soluble ActRIIA/IIB limit their therapeutic potential and highlight the need for new reagents that target specific ActRIIA/IIB ligands. Here, we modified the activin prodomains, regions required for mature growth factor synthesis, to generate specific activin antagonists. Initially, the prodomains were fused to the Fc region of mouse IgG2A antibody and, subsequently, “fastener” residues (Lys45, Tyr96, His97 and Ala98) that confer latency to other TGF-β proteins were incorporated. These modifications generated a reagent that potently (IC50 5nM) and specifically inhibited activin signaling in vitro, and activin-induced muscle wasting in vivo. Importantly, unlike soluble ActRIIA/IIB, the modified prodomains did not inhibit the activitiy of related ActRII ligands, myostatin or GDF-11. To underscore the therapeutic utility of specifically antagonising activin signalling, we demonstrate that the modified activin prodomains promote significant increases in muscle mass. Using a mouse xenograft model, we also showed that pharmacological delivery of the prodomains can prevent tumour-derived muscle wasting. Significantly, our novel activin therapeutic has exciting potential in the treatment of cancer-cachexia.