Biodegradable polymers have been broadly used as agents that can complex with and deliver osteoinductive agents, but osteoinductivity of the polymers themselves has been rarely studied. Here we report the osteoinductivity of poly(4-hydroxy-L-proline ester) (PHPE), a biodegradable cationic polymer with cell penetrating properties. Under physiological conditions, PHPE degrades into trans-4-hydroxy-L-prohne (trans-Hyp), a non-coded amino acid with essential functions in collagen fibril formation and fibril stability. Treatment of SaOS-2 osteoblast-like cells and hFOB 1.19 primary osteoblast cells with PHPE promoted earlier collagen nodule formation and mineralization of the extracellular matrix compared to untreated cells, even when mineralization activators were absent in the growth medium. Our results indicate that PHPE is a potential osteoinductive agent in vitro that can favor bone regeneration. Moreover, this osteoinductive property could be partly attributed to the degradation product trans-Hyp, which could recapitulate some, but not all of the osteogenic activity. The primary findings of this study can be summarized as follows: treatment of cells with PHPE led to (1) the induction of COL1A1 expression, collagen synthesis and secretion in osteoblast-like cells, (2) mineralization of the ECM in both SaOS-2 and hFOB 1.19 primary osteoblasts, and (3) induction of BMP2 gene and protein expression in osteoblast-like cells, which can promote mineralization of the ECM and regeneration of the bone tissue. Our results suggest that PHPE is a non-cytotoxic polymer and can be potentially used to overcome collagenopathies such as osteogenesis imperfecta.