Little is known about how surface topography can modulate mesenchymal cell responses to oxygen-related stress occurring with age, or during the early phases of wound healing or inflammation. To antagonize Reactive Oxygen Species (ROS), cells resort to defense mechanisms, relying on β-catenin, a molecular switch between a TCF-mediated pathway, which promotes cells proliferation and commitment, and an alternative one controlled by FoxO, which induces quiescence and defenses against ROS. In the present study, we show that mesenchymal C2C12 cells are protected from H₂O₂-induced oxidative stress when they grow on rough (SLA) titanium surfaces. The expression of anti-ROS genes and FoxO/β-catenin signaling, as measured by a reporter assay, were increased on SLA surfaces. We also show that TCF-mediated transcription was inhibited by ROS in cells growing on either smooth or SLA titanium. Our results demonstrate that surface topography modulates cell resistance to ROS and the balance between the molecular pathways regulating cell growth and cell defense against oxidative stress.