Aloe vera is a plant with a long history of traditional medicinal use and is consumed in different products, sometimes in conjunction with prescribed medicines. A. vera gel has shown the ability to modulate drug absorption in vitro. The aim of this study was to fractionate the precipitated polysaccharide component of A. vera gel based on molecular weight and to compare their interactions with indinavir pharmacokinetics. Crude polysaccharides were precipitated from a solution of A. vera gel and was fractionated by means of centrifugal filtration through membranes with different molecular weight cut-off values (i.e. 300 KDa, 100 KDa and 30 KDa). Marker molecules were quantified in the aloe leaf materials by means of nuclear magnetic resonance spectroscopy and the average molecular weight was determined by means of gel filtration chromatography linked to multi-angle-laser-light scattering and refractive index detection. The effect of the aloe leaf materials on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers as well as indinavir metabolism in LS180 cells was measured. The bioavailability of indinavir in the presence and absence of the aloe leaf materials was determined in Sprague-Dawley rats. All the aloe leaf materials investigated in this study reduced the TEER of Caco-2 cell monolayers, inhibited indinavir metabolism in LS 180 cells to different extents and changed the bioavailability parameters of indinavir in rats compared to that of indinavir alone. These indinavir pharmacokinetic modulation effects were not dependent on the presence of aloverose and also not on the average molecular weight of the isolated fractions.