Bipolar disorder (BD) has been associated with abnormalities in neuroplasticity and previous studies suggest an important role for BDNF in the pathophysiology of BD. The confounding effect of the use of medication in these studies has been considered a limitation. Thus, studies with both drug-free and medicated patients are necessary to assess the role of medication in serum BDNF levels. Twenty-two manic and depressed drug-free and 22 medicated BD type I patients were matched to 22 controls according to sex and age in a cross-sectional study. BDNF serum levels were assessed using sandwich-ELISA. Serum BDNF levels in drug-free (0.23+/-0.09), and medicated (0.29+/-0.19) BD patients were decreased when compared to controls (0.40+/-0.12) - drug-free/medicated vs. control p<0.001. The BDNF levels did not differ between medicated and drug-free BD patients. When analyzing patients according to mood states, serum BDNF levels were lower in BD patients during both manic (0.28+/-0.11) and depressive episodes (0.22+/-0.17), as compared with healthy controls (0.40+/-0.12) - manic/depressed patients vs. controls p<0.001. Results suggest that the association of lower serum BDNF and BD mood episodes is kept even in medicated patients, which strengthens the notion that BDNF serum levels may be considered a biomarker of mood episodes in BD.