Mild traumatic brain injury (MTBI) is a major public health problem in the United States. A significant subset of MTBI patients develop persistent and distressing neurological, cognitive, and behavioral symptoms, known as the post-concussion syndrome (PCS). To date, multiple studies have assessed the relationship between brain-related proteins found in the serum at the time of injury, and the development of PCS. We conducted a systematic review of prospective cohort studies that assessed the ability of serum biochemical markers to predict PCS after MTBI. A total of 11 studies assessing three different potential biochemical markers of PCS--S100 proteins, neuron-specific enolase (NSE), and cleaved Tau protein (CTP)--met selection criteria. Of these markers, S100 appeared to be the best researched. We conclude that no biomarker has consistently demonstrated the ability to predict PCS after MTBI. A combination of clinical factors in conjunction with biochemical markers may be necessary to develop a comprehensive decision rule that more accurately predicts PCS after MTBI.