Although maternal low density lipoprotein (LDL) is the primary source of cholesterol substrate for progesterone biosynthesis in the primate placental syncytiotrophoblast, the hypothesis to be tested is that the baboon trophoblast may derive significant amounts of substrate from sources secondary to the classical LDL pathway during early pregnancy or when faced with a paucity of lipoprotein-cholesterol. Expression of LDL receptor mRNA in syncytiotrophoblasts, assessed by reverse transcriptase-polymerase chain reaction (RT-PCR), was greater (P $<$ 0.05) in late than in early baboon pregnancy, although no difference was observed in whole villous tissue. Divergently, both enzyme activity and protein levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in syncytiotrophoblast cells were higher (P $<$ 0.01) in early than in late pregnancy, while mRNA concentrations were unchanged with advancing gestation. Abundance of scavenger receptor-I (SR-I) mRNA was low in baboon placenta. Scavenger receptor-II (SR-II) mRNA concentrations in syncytiotrophoblast cells were two-fold higher than in whole villous tissue, in contrast to LDL receptor related protein (LRP) mRNA concentrations, which were higher in whole villous tissue than in syncytiotrophoblasts Cholesterol yielding pathways were also investigated in pregnant baboons via treatment with 4-aminopyrazolo (3-4-d) pyrimidine (4-APP, an inhibitor of hepatic lipoprotein production). Thus, LDL-cholesterol concentrations were dramatically lower (P $<$ 0.005) and commensurate progesterone levels also lower (P $<$ 0.03) in 4-APP treated baboons than in untreated baboons. A potential enhancement of LDL receptor (mRNA) and HMG-CoA reductase (mRNA, protein and enzyme activity), as well as a decline in acyl-coenzyme A:cholesterol acyl transferase (mRNA) in the baboon syncytiotrophoblast, probably resulted from 4-APP induced lipoprotein withdrawal and constitute the first demonstration of this compensatory mechanism in the primate placenta In conclusion, secondary cholesterol-yielding mechanisms in the syncytiotrophoblast may provide significant amounts of cholesterol substrate for progesterone production during early baboon pregnancy and when the availability of lipoprotein-cholesterol substrate is reduced. Further, mechanisms responsible for cholesterol homeostasis in the steroidogenically active syncytiotrophoblast are regulated in a divergent manner from those in proliferative nonendocrine components of the placenta