A steady-state physiological flow model has been developed for predicting plasma free serotonin (5-HT), and platelet 5-HT, concentrations in man. The basic assumptions of the model are that 5-HT is produced in the wall of the intestine, enters the portal circulation at a constant rate, and is cleared by the lung, liver, kidney, and capillary bed. When a priori best estimates of the 5-HT production rate and organ extraction efficiencies were substituted into formulae describing the model, a predicted value for plasma free 5-HT of 304 pg/ml was obtained, in good agreement with a previously observed mean (+/- SE) of 387 +/- 84 pg/ml. The effects of varying production rate and extraction efficiency parameters on predicted levels of plasma free 5-HT are examined. The practical implications of the model and its possible utility in elucidating the causes of altered plasma free or platelet 5-HT seen in certain conditions are discussed.