Background <p>Major Depressive Disorder (MDD) is a prevalent condition characterized by alterations in different biological systems including inflammatory and antioxidant pathways. Antidepressants seem to rebalance biological abnormalities. In this short communication, we report differences in a set of biomarkers between drug-free patients and those who benefited from response to antidepressant monotherapy.</p> Methods <p>A sample of patients affected by MDD (<i>N</i> = 38) was recruited at the inpatient and outpatient clinic of Policlinico Hospital in Milan: 26 responders and 12 drug-free subjects. The two groups of patients were compared by χ2 tests and analyses of variance, respectively, for qualitative and continuous variables. Correlation analyses were performed to evaluate the relationship between rating scale scores (severity of MDD) and biological parameters.</p> Results <p>Drug-free patients (compared to the counterpart) had a higher number of previous suicide attempts (<i>p</i> &lt; 0.01), lower levels of plasmatic proteins (<i>p</i> &lt; 0.01), albumin (<i>p</i> = 0.02), and total cholesterol (<i>p</i> = 0.02), but higher plasma levels of dehydroepiandrosterone sulfate (DHEAs) (<i>p</i> = 0.02), adrenocorticotropic hormone (ACTH) (<i>p</i> &lt; 0.01) and angiotensin converting enzyme (ACE) (<i>p</i> = 0.02).</p> Conclusions <p>The results of the present study suggest that the severity of MDD is associated with more prominent biological changes, and antidepressants might mitigate these abnormalities. Future studies with larger samples are needed to confirm these preliminary findings.</p>