Transforming growth factor-beta (TGF-beta) is present at high concentrations in maternal milk. In milk TGF-beta2 is the predominant isoform. For function TGF-beta2 requires TbetaRIII to facilitate efficient binding to the TGF-beta receptor types I and II signalling complex. We have shown that TGF-beta receptor types I (TbetaRI), II (TbetaRII) and III (TbetaRIII) are coexpressed in the suckling rat intestine. Immunostaining for TbetaRIII was also observed in the intestinal lumen prior to weaning. TbetaRIII (or betaglycan) has been reported in serum, cell culture medium and extracellular matrix. To determine whether a soluble form of TbetaRIII is present in milk, the rat milk aqueous phase was analysed by slot-blot and Western blot. Soluble TbetaRIII was detected in milk throughout lactation. Western blot analysis of rat milk revealed a high molecular weight band of glycosylated protein of >200 kDa, with a core protein of approximately 110-120 kDa that comigrated with recombinant TbetaRIII. Immunoabsorption of soluble TbetaRIII (sTbetaRIII) from milk resulted in partial depletion of active TGF-beta from milk, suggesting that the receptor may interact with ligand in milk. In addition rat pups suckled on mother's milk demonstrated an enhanced labelling of TbetaRIII in the gut, as compared with pups fed on a rat milk substitute (RMS). These findings suggest that milk sTbetaRIII is functional, and may modulate milk-derived TGF-beta function in the developing intestine.