This study investigated the effect of two different activation methods on the surface chemical composition of a CoCrMo-alloy. The activation was performed with oxygen plasma (OP) or nitric acid (NA). The surface physical– chemical properties were thoroughly characterized by means of several analytical techniques: X-ray photoelectron spec- troscopy (XPS), time-of-flight secondary ion mass spec- trometry (ToF-SIMS), zinc-complex substitution technique, contact angle, and interferometry. The surface modification was evaluated by assessing contamination removal, the ‘‘active’’ hydroxyl groups (OH-act) present at the surface, the metal oxide ratio (Co y O x - /Cr y O x - ) and changes in the chem- ical composition and topography of the oxide layer. XPS experimental data showed for both methods (OP and NA) a significant decrease of the carbon contents (C 1 s ) associated with contaminants and at the same time changes in the atomic composition of the oxide layer (O 1 s ). In addition, the O 1 s XPS spectra showed differences between the percentage of OH - before and after OP or NA treatment, leading to the conclusion that both methods are effective for surface ‘‘cleaning’’ and activation. These results were further inves- tigated and corroborated by ToF-SIMS analysis and zinc complex substitution technique. The general conclusion was that NA is more efficient in terms of contaminants removal and generation of accessible OH-act present at the surface and without altering the native metal oxide ratio (Co y O x - /Cr y O x - ) considered to be essential for biocompatibility.