Carbon monoxide (CO) poisoning resulting in diffuse tissue hypoxia. Cerebral hypoxia is a major cause of morbidity and mortality after CO poisoning. There are some clinical criteria that could help a physician to make a decision concerning the application of hyperbaric oxygenation therapy. However, it would be convenient to discover an objective biochemical serum marker that could help in the grade evaluation of CO poisoning and indication of therapy in CO-poisoned patients. We present two case reports where the established criteria for the CO poisoning were not optimum for the decision regarding therapy. It seems that the S-100B protein could be used as a biochemical marker of CO induced brain injury. S-100B values could perhaps help us to select patients for hyperbaric oxygen therapy and to predict the short and long term outcome.