Objectives. To determine whether a molecular signature is present in blood of patients with psychiatric disorders before manifestation of symptoms. Methods. Multiplex immunoassay analyses were carried out using serum obtained from two case-control studies of schizophrenia (n = 75) and bipolar disorder (n = 110) patients and their matched controls. The samples were drawn within 1 month before estimated onset of illness. Results. This led to identification of 20 molecules which were altered in pre-schizophrenia and 14 molecules in pre-bipolar disorder subjects compared to controls. Only two of these molecular changes were identical in both data sets and predictive testing confirmed that the biomarker signatures for pre-schizophrenia and pre-bipolar disorder were dissimilar. Conclusion. The present results suggest that there are distinct serum alterations that occur before clinical manifestation of schizophrenia and bipolar disorder. These findings could lead to development of diagnostic tests to help clinical psychiatrists identify and classify vulnerable patients early in the disease process, allowing for earlier and more effective therapeutic intervention.