It is important to differentiate between bipolar disorder (BD) and major depressive disorder (MDD) in the first depressive episode because of the potential treatment implications. Previous studies have mainly focused on the different clinical features or pathological biomarkers to distinguish these two diseases; however, a better understanding of the proteomics profiling of BD may help aid future therapeutic strategies. Here, we applied isobaric tags for relative and absolute quantification (iTRAQ) technology combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins between MDD and bipolar depression (BP). In total, 30 MDD, 30 BP and 30 healthy subjects were included. Proteins from depleted plasma samples were digested into peptides, individually labeled with iTRAQ reagents, combined and subjected to LC-MS/MS and further bioinformatics analyses. Our results showed that 9 proteins were significantly altered between MDD and BP. Briefly, B2RAN2, B4E1B2, APOA1, ENG, SBSN and QSOX2 were up-regulated, whereas ORM1, MRC2 and SLPI were down-regulated. Most identified proteins were related to the immune system. The bioinformatics analysis showed that B2RAN2 (highly similar to vanin-1) was involved in the significantly enriched KEGG pathways "pantothenate and CoA biosynthesis" (P=0.009). B2RAN2 and ENG may play important roles in depression. They may serve as candidate biomarkers for distinguishing MDD and BP. Further validation and investigation are required to illuminate the roles of B2RAN2 and ENG in MDD and BP. The current study provided a potential and novel biomarker panel that may, in turn, aid the diagnosis of BD.