Extracellular matrix is the biological scaffold which provides both structural support as well as factors which support cellular differentiation and tissue/organ function. Cytotrophoblasts (CTB) are the epithelial stem cells in the placenta which can give rise to both villous syncytiotrophoblast (STB) and invasive extravillous trophoblast (EVT). Modified differentiation of CTBs resulting in too few EVTs underlies the abnormalities and symptoms observed in preeclamptic placentas. Studies investigating the plating of progenitor cells on their tissue-specific ECM demonstrated the effect of ECM on cellular processes such as differentiation, proliferation, survival, and adhesion. The results of the study presented here reveal for the first time that primary CTBs can be maintained in an undifferentiated state when cultured on human placental ECM. ECM was prepared from minced third trimester placental tissues following decellularization, detergent washes and nucleic acid treatment. The resulting matrix was dehydrated by a lyophilizer and reconstituted in 0.1M acetic acid before plating. Through the novel approach of decellularizing a human placenta, it was found that clinically normal placentas had 3.64 times higher ECM yield than preeclamptic placentas. Primary CTBs were isolated from term placental tissues per published protocols and cultured either on tissue culture plastic as a control, or 1 mg/mL placental ECM. Differentiation was monitored based on morphology, hCG production, and qPCR for lineage-specific markers. Primary CTBs were also monitored for ECM effects on cell proliferation, apoptosis, and adhesion. With isolated term CTBs, cells plated on placental ECM, both normal (nlECM) and preeclamptic (peECM) mostly remained mononuclear, produced significantly less hCG, and showed significantly lower expression of markers of STB differentiation, including hCG_, hCG_, Syncytin, and CSH-1 by qPCR. This study demonstrates that placental extracellular matrix can maintain the undifferentiated state of primary CTBs, while having little to no effect on proliferation, survival, and adhesion. This study also suggests that composition of the extracellular matrix does not play a substantial role in driving modified trophoblast differentiation observed in preeclamptic placenta.