Thermal oxidation of porous silicon (pSi) has been used to control interactions with three proteins; lysozyme, papain, and human serum albumin (HSA) enabling the influences of protein structure, molecular weight, and charge to be elucidated. Adsorption behavior was assessed via adsorption isotherms while the structures of adsorbed proteins were investigated using a bioactivity assay, FTIR, and zeta potential. Time-of-flight secondary ion mass spectrometry was used to examine protein pore penetration. High protein adsorption onto unoxidized pSi (240-610 microg/m(2)) was attributed to predominately hydrophobic interactions which resulted in structural changes of the adsorbed proteins and significant loss of bioactivity. Thermal oxidation at 400 and 800 degrees C significantly reduced protein adsorption (80-485 microg/m(2)) by reducing hydrophobicity. Oxidation of pSi modified the protein adsorption mechanisms to solely electrostatic attraction for positively charged proteins and structural rearrangement for negatively charged proteins. Adsorption via electrostatic attraction preserved protein bioactivity and zeta potential, thus inferring a retention of their native structure. In contrast, the negative charge and globular structure of HSA resulted in a loss of structure. We have demonstrated that thermal oxidation of pSi can be used to control protein interactions, adsorbed structure, and bioactivity.