Surface modification of polymethyl methacrylate (PMMA) by O-2/CF4 plasma is investigated to improve hydrophilicity and antifouling performance of PMMA. The PMMA surface before and after treatment is characterized by atomic force microscopy, contact angle measurement, and X-ray photoelectron spectroscopy. Antifouling properties are evaluated by protein adsorption and bacterial adhesion experiments using Staphylococcus aureus in vitro. Higher O-2 content in the mixture gas promotes hydrophilicity of the plasma-treated PMMA, while a hydrophobic surface forms at higher CF4 content. Modifying PMMA improves antifouling performance regardless of the O-2/CF4 volume ratio, and this improvement increases with rising CF4 content in O-2/CF4 plasma working gas. Functional groups C-O and C-F are detected in O-2/CF4 plasma-treated PMMA surface and the ratio of C-O to C-F can be controlled by the O-2/CF4 volume ratio in the plasma working gas.