Schizophrenia is a severe psychotic illness affecting 1% of the population. There are no consistent pathological features and the disorder is defined by a complex symptomatology, which overlaps with other psychiatric illnesses. Rapid and effective treatment has been shown to improve disease outcome. It is therefore important to identify disease-associated biomarkers facilitating early diagnosis. Proteins from anti-CD3 stimulated and unstimulated peripheral blood T cell lysates from 15 patients and 15 matched controls were profiled on cation exchange (CM10) chips, using surface enhanced laser desorption ionization (SELDI) mass spectrometry. Partial least squares discriminate analysis (PLS-DA) was used to separate patient and control groups according to the expression of 108 detected peaks. Two peaks of 3374 Da and 3450 Da, corresponding to alpha defensins based on masses and cationic properties, contributed significantly to the separation of patient and control groups. Dithiothreitol (DTT) reduction of T cell lysates resulted in a 6 Da shift in peak masses, consistent with the presence of 3 cysteine bonds in the structure, confirming them as alpha defensins. Alpha defensins were quantified in T cell lysates from 6 patients and 18 controls and in plasma from 21 pairs of monozygotic twins discordant for schizophrenia by ELISA. Alpha defensins were significantly increased in patient lysates compared to matched controls (p= 0.0197) and intriguingly, both affected and unaffected twins were found to have significantly elevated alpha defensins compared to healthy control twin pairs (p=0.0014 and p=0.0115 respectively). Significantly increased expression of alpha defensins in both unaffected and schizophrenic twins is of particular interest as monozygotic twins share genes and environmental upbringing. The unaffected twin therefore represents the biological and environmental risk of developing schizophrenia in the absence of overt symptomatology and therapeutic medication. These findings suggest that alpha defensins could be an important early indicator of the risk of schizophrenia.