Background: The calcium binding protein S100B and brain derived neurotrophic factor (BDNF) are both bio-markers implicated in neuronal processes in the central nervous system and seem to be associated with affective disorders. Here we investigated both markers in a sample of monozygotic (MZ) twins with, at risk of and without affective disorders, aiming to evaluate whether these markers have a role as causal factors-or trait markers for affective disorders. Method: We measured serum S100B and plasma BDNF levels in 204 monozygotic twins (MZ) with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). Results: No significant group differences in S100B and BDNF levels were found between the three groups. Exploratory analysis revealed that higher S100B levels were correlated with lower cognitive performance. Limitations: The cross-sectional design cannot elucidate the two neuronal biomarkers role as causal factors. We would have preferred a higher sample size in the high-and low-risk groups. Conclusion: The present result did not support a role for S100B and BDNF as neither causal factors nor trait markers for affective disorders. Elevated S100B levels may associate with impaired cognition, but further studies are warranted.