In Life Cycle Assessment and Comparative Risk Assessment potential human exposure to toxic pollutants can be expressed as the human intake fraction (iF), representing the fraction of the quantity emitted that enters the human population. To assess model uncertainty in the human intake fraction, ingestion and inhalation iFs of 367 substances emitted to air and freshwater were calculated with two commonly applied multi-media fate and exposure models, CalTOX and USES-LCA. Comparison of the model outcomes reveal that uncertainty in the ingestion iFs was up to a factor of 70. The uncertainty in the inhalation iFs was up to a factor of 865,000. The comparison showed that relatively few model differences account for the uncertainties found. An optimal model structure in the calculation of human intake fractions can be achieved by including (1) rain and no-rain scenarios, (2) a continental sea water compartment, (3) drinking water purification, (4) pH-correction of chemical properties, and (5) aerosol-associated deposition on plants. Finally, vertical stratification of the soil compartment combined with a chemical-dependent soil depth may be considered in future intake fraction calculations.