Major depressive disorder (MDD) is a debilitating disorder whose etiology remains unclear. Small RNA molecules, such as microRNAs (miRNAs), have been implicated in MDD, where they display differential expression in the brain and periphery. Hence, numerous studies have identified altered gene expression and changes in anterior cingulate cortex (ACC) activity in MDD, which appear to be related to antidepressant treatment response. Here, we quantified miRNA expression by small RNA sequencing in the ventromedial prefrontal cortex (vmPFC) of individuals with MDD/suicide and healthy controls. miRNA expression was measured in the vmPFC of 17 antidepressant-free depressed suicide patients (7F/10M) and 17 well-matched non-psychiatric controls (7F/10M) using miRNA sequencing. We found significant changes in total miRNA expression in vmPFC of depressed suicide subjects. Individual tests for statistical significance (p≤0.05) revealed that 17 miRNAs were downregulated while 17 miRNAs were upregulated. Furthermore, we found that miR-1290 and miR-1246 levels were increased in the male suicidal depressive group, whereas female suicidal depressive subjects showed decreased levels of miR-4516 and miR-10400 and increased levels of miR-483. In addition, we detected differential expression of certain miRNAs not previously reported in patients with MDD, including miR-320d, miR-1299, and miR-151b. We identified several miRNAs that showed increased or decreased levels in the vmPFC of individuals with depression and suicide. In addition, we found sex-dependent changes in some miRNAs. Future studies should better characterize functional miRNA-mRNA interactions. Normalizing the levels of these miRNAs using miRNA-loaded nanoparticles may be a therapeutic strategy for depression/suicide, which we are currently working on.