All major classes of normal circulating lipoproteins can be metabolized by human placental cells. However, the metabolism of abnormal or modified lipoproteins has been little studied. We therefore investigated whether placental cells metabolize acetylated low density lipoprotein (ac-LDL) or oxidatively-modified LDL (ox-LDL), both of which are metabolized by scavenger receptors, and if so, whether modified LDL stimulates progesterone secretion as does normal LDL. Placental macrophages and trophoblasts were isolated on a 40% Percoll gradient after enzymatic digestion. The cellular uptake and degradation of [125I]-ac-LDL was 20-fold higher than [125I]-LDL in both macrophages and trophoblasts. Both cell types demonstrated high affinity and saturable degradation. Similarly, increased esterification of [14C]-labelled oleic acid to cholesterol was observed when cells were incubated with ac-LDL vs. LDL. Uptake of ac-LDL by trophoblasts also was demonstrated by colocalization of fluorescently labelled ac-LDL and fluorescent antibodies specific for trophoblasts. Similar colocalization of fluorescent ac-LDL and fluorescent anti-macrophage specific epitopes was seen in macrophages. Uptake and degradation of [125I]-ac-LDL by placental cells was inhibited by increasing concentrations of unlabelled ac-LDL or fucoidin but not LDL, indicating uptake by a scavenger receptor. Both unlabelled ac-LDL and ox-LDL inhibited uptake of [125I]-labelled ox-LDL, suggesting uptake by a common mechanism. Although secretion of progesterone by trophoblasts was stimulated by incubation with LDL, progesterone secretion by trophoblasts was not stimulated by ac-LDL and only minimally stimulated by ox-LDL. CONCLUSIONS Scavenger receptors are present in human placental trophoblasts as well as macrophages. Scavenger receptor activity greatly exceeds that of LDL receptor activity in both cell types. However, cholesterol assimilated via the scavenger receptor pathway appears to be disconnected from endocrine steroidogenesis in trophoblasts. Thus, we hypothesize that scavenger receptors function in trophoblasts to degrade modified lipoproteins and prevent toxic effects on placental cellular function and fetal growth and development.