Background: The development of complex diseases is contributed by the combination of multiple factors and complicated interactions between them. Inflammation has recently been associated with many complex diseases and may cause long-term damage to the human body. In this study, we examined whether two types of complex disease, cerebrovascular disease (CVD) or major depression (MD), systematically altered the transcriptomes of non-diseased human tissues and whether inflammation is linked to identifiable molecular signatures, using post-mortem samples from the Genotype-Tissue Expression (GTEx) project. Results: Following a series of differential expression analyses, dozens to hundreds of differentially expressed genes (DEGs) were identified in multiple tissues between subjects with and without a history of CVD or MD. DEGs from these disease-associated tissues—the visceral adipose, tibial artery, caudate, and spinal cord for CVD; and the hypothalamus, putamen, and spinal cord for MD—were further analyzed for functional enrichment. Many pathways associated with immunological events were enriched in the upregulated DEGs of the CVD-associated tissues, as were the neurological and metabolic pathways in DEGs of the MD-associated tissues. Eight gene-tissue pairs were found to overlap with those prioritized by our transcriptome-wide association studies, indicating a potential genetic effect on gene expression for circulating cytokine phenotypes. Conclusion: Cerebrovascular disease and major depression cause detectable changes in the gene expression of non-diseased tissues, suggesting that a possible long-term impact of diseases, lifestyles and environmental factors may together contribute to the appearance of “transcriptomic scars” on the human body. Furthermore, inflammation is probably one of the systemic and long-lasting effects of cerebrovascular events.