The hydroxyl radical is the most reactive oxygen species, and it is able to attack macromolecules such as proteins. Such oxidation processes are the cause of a number of diseases. Several oxidized products have been experimentally characterized, but the reaction pathways remain unclear. Herein, we present a theoretical study on the attack of hydroxyl radicals on hydroxyl- and sulfur-containing amino acid side chains. Several reaction mechanisms, such as hydrogen abstraction, electron transfer, or center dot OH addition have been considered to investigate several reaction mechanisms. Two different dielectric values (4 and 80) have been used to model the effect of different protein environments. In addition, different alternative conformations of the amino acid backbone have been considered. Overall, the results indicate that the thermodynamics is the main factor driving the reaction pathway preference and, to a great extent, explains the formation of the experimental oxidized produts. Sulfur-containing amino acids would be oxidized more easily than OH-containing amino acids, which confirms the experimental evidence This is determined by the stability of the sulfur radical intermediates. These results are not dramatically affected by either different dielectrics or backbone