The inhibition of 5-[3H]hydroxytryptamine uptake into rat forebrain synaptosomes by human plasma extracts was studied. Highly potent, small (Mr less than 10 000), and heat stable factor(s) were found to inhibit 5-[3H]hydroxytryptamine uptake specifically, reversibly and in a non-competitive manner. The possible role of these factor(s) as endogenous modulators of serotonergic activity is discussed.