In addition to their solubilising properties, excipients used in lipid-based formulations (LBFs) can improve intestinal permeability of macromolecules. We determined whether ad-mixing of medium chain fatty acid (MCFA) permeation enhancers (PEs) with a lipoidal excipient (Labrasol®) could potentiate trans-epithelial flux of a poorly permeable macromolecule (FITC-dextran 4 kDa, FD4) across rat intestinal mucosae mounted in Ussing chambers. Low concentrations of sodium caprate (C10), sodium undecylenate (C11:1), or sodium laurate (C12) combined with Labrasol® increased the Pappof FD4 to values typically seen with higher concentrations of MCFAs or Labrasol® alone. For example, combination of C11:1(0.5 mg/mL) with Labrasol® (1 mg/mL) increased the Pappof FD4 by 10- and 11-fold over the respective individual agents at the same concentrations where no enhancement was evident. The increased enhancement ratios seen with the combinations were associated with some perturbation in intestinal histology and with attenuation of an epithelial functional measure, carbachol-stimulated inward short-circuit current (Isc). In conclusion, combining three MCFAs separately with Labrasol® increased the Pappof FD4 to values greater than those seen for MCFAs or Labrasol® alone. Ultimately, this may permit lower concentrations of MCFA to be used in combination with other excipients in oral formulations of poorly permeable molecules.