Updated project metadata. Depression is a complex and multifactorial disease, affecting about 6.5% of the elderly population in what is referred to as late-life depression (LLD). Despite its public health relevance, there is still limited information about the molecular mechanisms of LLD. We analyzed the blood plasma of 50 older adults through untargeted mass spectrometry and used systems biology tools to identify biochemical pathways and biological processes dysregulated in the disease. We found 96 differentially expressed proteins between LLD patients and control individuals. Using elastic-net regression, we generated a panel of 75 proteins that comprises a potential model for determining the molecular signature of LLD. We also showed that biological pathways related to vesicle-mediated transport and voltage-dependent calcium channels may be dysregulated in LLD. These data can help to build an understanding of the molecular basis of LLD, offering an integrated view of the biomolecular alterations that occur in this disorder.