Polymeric tissue-engineering scaffolds must provide mechanical support while host-appropriate cells populate the structure and deposit extracellular matrix (ECM) components specific to the organ targeted for replacement. Even though this concept is widely shared, changes in polymer modulus and other mechanical properties versus biological exposure are largely unknown. This work shows that specific interactions of biological milieu with electrospun scaffolds can exert control over scaffold modulus. The net effects of biological and non-biological environments on electrospun structures following 7 and 28 days of in vitro exposure are established. Reduction of modulus, ultimate tensile strength and elongation occurs without the apparent involvement of classic hydrolysis mechanisms. We describe this phenomenon as deposition-induced inhibition of nanofiber rearrangement. This phenomenon shows that both mechanical and morphological characterization of electrospun structure under load in biological environments is required to tailor scaffold design to pursue specific tissue-engineering goals.