Biomaterial nanotopographies have been proposed as a means to significantly influence cell functions (including osteoblasts, fibroblasts, endothelial cells, chondrocytes, immune cells, and bacteria). In this study, lung epithelial carcinoma cell functions including adhesion (up to 4 h), proliferation (up to 3 days), apoptosis (up to 5 days), and vascular endothelial growth factor (VEGF) synthesis (up to 5 days) on poly-lactic-co-glycolic (PLGA) films with various nanotopographies were systematically investigated. Importantly, this study created PLGA films with various nanotopographies (specifically, nano-smooth, 23, 300, and 400 nm hemispherical surface features) but similar surface chemistry in order to focus only on the effect of PLGA topography on cancer cell functions. Simple and effective cast-molding and solvent evaporation methods were used to accomplish this. Atomic force microscopy, electron spectroscopy for chemical analysis, and water contact angle measurements verified similar surface chemistry and energy but varied topographies for all of the PLGA films prepared in this study. Lung epithelial carcinoma cell adhesion, proliferation, and morphology results indicated less cell growth and spreading on nano-smooth and 400 nm surface-featured PLGA compared to any other samples. However, results also demonstrated decreased lung epithelial carcinoma cell VEGF (a key growth factor secreted for the vascularization of tumors) synthesis on the 23 nm surface-featured PLGA compared to the nano-smooth substrates for up to 5 days. In summary, these results provided the first insights into understanding the role that PLGA nanotography may play in mediating lung carcinoma cell functions for a wide range of applications in regenerative medicine. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2012.