Treatment of human neutrophils and monocytes with human plasma fibronectin (Fn) enhanced their association with Trypanosoma cruzi epimastigote culture forms, a stage of parasite which activates the alternative complement pathway, and this related to the concentration of Fn in the culture medium. By increasing the incubation time, the parasite interiorization by phagocytic cells was observed. An enhancing effect of this latter phenomenon was obtained in the presence of Fn, while the addition of anti-Fn antibodies exerted an inhibitory effect. Moreover, the velocity of phagocytosis of complement-coated epimastigotes in the presence of Fn appeared greater than that observed using non-coated epimastigotes or parasites preincubated in the presence of heat-inactivated C6-deficient rabbit serum. In addition, as a consequence of cell-Fn parasite interaction, cell activation was also seen. This has been demonstrated by a chemiluminescence assay. Using radiolabeled epimastigotes (3H-uridine), we demonstrated that a proportion of ingested parasites in the presence of Fn were killed. When neutrophils were used as effector cells, the cytotoxicity was greater than that observed with monocytes. This finding of increased trypanosome uptake by phagocytic cells in the presence of fibronectin suggests that this glycoprotein could act as a ligand or cofactor to mediate parasite-cell interaction.