Background <p>Brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of neuronal plasticity in the central nervous system. Successful biological interventions upregulate the expression of BDNF in generalized anxiety disorder (GAD) patients, but no study of psychological treatments has been found. The present study aimed to evaluate changes in plasma BDNF levels following two psychological treatments with established clinical efficacy in patients with GAD. Methods: Participants were recruited for a 14-week, 10-session clinical trial of either group acceptance-based behavior therapy (ABBT) or supportive therapy (ST). Eligible patients were GAD patients aged 18–65 years. Plasma BDNF was measured in 82 patients before and after the intervention (ABBT = 41, ST = 41). Correlation with anxiety symptom severity was also assessed using the Hamilton Anxiety Scale at pre- and post-treatment. Results: BDNF increased in both groups over time (ST: difference = 2042.6, t = 4.81, <i>p</i> &lt; 0.001 vs. ABBT: difference = 1947.8, t = 4.46, <i>p</i> &lt; 0.001). Although anxiety symptoms decreased in both groups, no correlation between BDNF and anxiety severity was found. Conclusions: The present study suggests that a short-term trial of two clinically effective psychotherapeutic interventions was associated with increases in plasma BDNF levels in GAD patients. Given the absence of associations between BDNF changes and symptom severity, these findings should be interpreted cautiously and not as evidence of treatment-specific or mechanistic effects.</p> Trial registration <p>NCT03930095||<a href="https://www.clinicaltrials.gov">https://www.clinicaltrials.gov</a>/ retrospectively registered on 15 April 2019.</p>