In this study, we evaluate coaxial electrospun nanofibers, with gelatin in the shell and poly(vinyl alcohol) (PVA) in the core as a potential vascular material by determining fiber surface roughness, as well as human platelet deposition and activation under varying conditions. PVA scaffolds had the highest surface roughness (Ra = 65.5 +/- 6.8 nm) but the lowest platelet deposition (34.2 +/- 5.8 platelets) in comparison to gelatin nanofibers (Rat = 36.8 +/- 3.0 nm and 168.9 +/- 20 platelets) and coaxial nanofibers (1 Gel:1 PVA coaxial, Ra = 24.0 +/- 1.5 nm and 150.2 +/- 17.4 platelets. 3 Gel:1 PVA coaxial, Ra = 37.1 +/- 2.8 nm and 167.8 +/- 15.4 platelets). Therefore, the chemical structure of the gelatin nanofibers dominated surface roughness in platelet deposition, Due to their increased stiffness, the coaxial nanofibers had the highest platelet activation rate, rate of thrombin formation, in comparison to gelatin and PVA fibers. Our studies indicate that mechanical stiffness is a dominating, factor for platelet deposition and activation, followed by biochemical signals, and lastly surface roughness. Overall, these coaxial nanofibers are an appealing material for vascular applications by supporting cellular growth while minimizing platelet deposition and activation.