Some preclinical and postmortem studies suggest that the effects of atypical antipsychotics could be mediated by brain-derived neurotrophic factor (BDNF). Olanzapine is an atypical antipsychotic with shown efficacy in psychosis treatment. The aim of this study was to compare plasma BDNF levels at baseline and after 1 year of olanzapine treatment in 18 drug-naive patients who experienced a first psychotic episode with those of 18 healthy control participants matched by age, sex, and socioeconomic level. Plasma BDNF levels were measured in patients at the index episode and at 1, 6, and 12 months of follow-up using an enzyme-linked immunosorbent assay. Symptoms and functioning of patients and controls were assessed with the Positive and Negative Symptom Scale and Global Assessment of Function Scale. BDNF levels of patients at onset were significantly lower than controls but increased toward control values during olanzapine treatment. There was a significant positive correlation between BDNF levels and functioning (Global Assessment of Function Scale). BDNF levels were also negatively correlated with positive symptoms, but not with negative symptoms or general psychopathology. Results suggest that olanzapine can offset the low BDNF levels at the onset of first psychotic episodes, and improving psychotic symptoms. The increase in BDNF levels may be its mechanism of action in improving positive symptoms.