To investigate the role of chemical cross-links in regulating biomaterial properties and cell behavior, we have prepared and characterized a series of biodegradable polymer blends in both un-cross-linked and photo-cross-linked forms. In this comparative study, these blends consisted of an oligomeric, cross-linkable, amorphous poly(propylene fumarate) (PPF) and a high-molecular-weight, semicrystalline poly(ε-caprolactone) (PCL). After cross-linking, semi-interpenetrating polymer networks (semi-IPNs) were formed by combining PPF chemical network and PCL physical network that was associated by the crystallites. The material design strategy presented here was different from previously studied semicrystalline polymer networks, in which crystallizable segments participated covalently in the chemical network and were significantly suppressed by the network. For these PPF/PCL blends, thermal properties such as melting temperature (T(m)) and crystallinity have been correlated with their rheological and mechanical properties to demonstrate the effects of cross-linking density and crystallinity. Surface morphology, hydrophilicity, and the capability of adsorbing proteins from cell culture media have also been determined. For potential applications in bone and vascular tissue engineering and demonstration of regulating cell behavior on polymer substrates with controllable physicochemical characteristics, in vitro cell studies that included cell viability, attachment, spreading, and proliferation have been performed using mouse MC3T3 cells and primary rat aortic smooth muscle cells (SMCs). In a similar manner, these two cell types have been found to show distinct cell responses to the polymer substrates in the presence or absence of cross-links.