Background Growing evidence shows that the etiological causes and pathological processes underlying major depressive disorder (MDD) and schizophrenia (SCZ) overlap. Our previous study revealed a strong association between the polymorphism ss178077483 in the miRNA-30e precursor (pre-miR-30e) and the risk of SCZ. We thus hypothesized that this SCZ risk allele at the pre-miR-30e gene also confers risk of MDD. Methods To explore the relationship between miR-30e ss178077483 and MDD, we conducted an association analyses in 1088 MDD patients and 1102 control subjects from the Han Chinese population. We also determined the effects of miR-30e ss178077483 on the development of P300 event-related potential components induced by an auditory odd-ball task. Results We detected a statistically significant positive association between miR-30e ss178077483 and MDD (allelic P = 0.0287; genotypic P = 0.0275). Moreover, the P300 latency was associated with miR-30e ss178077483 genotypes and the individuals with the C/T genotype have a longer P300 latency than those carrying the C/C genotype ( P = 0.009). Limitations Larger numbers of subjects and different ethnic groups would confirm and strengthen these preliminary findings. Conclusions To our knowledge, this is the first evidence to suggest that miRNA polymorphisms may play an important role in MDD susceptibility. These findings also imply that certain miRNAs may be involved in the etiology of MDD.