Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and demonstrate endocrine and molecular alterations compared to controls. This study reports the association between parental Holocaust exposure and genome-wide gene expression in peripheral blood mononuclear cells (PBMC) from 77 Holocaust survivor offspring and 15 comparison subjects. Forty-two differentially expressed genes (DEGs) were identified in association with parental Holocaust exposure (FDR-adjusted p < 0.05); most of these genes were downregulated and co-expressed in a gene network related to immune cell functions. When both parental Holocaust exposure and maternal age at Holocaust exposure shared DEGs, fold changes were in the opposite direction. Similarly, fold changes of shared DEGs associated with maternal PTSD and paternal PTSD were in opposite directions, while fold changes of shared DEGs associated with both maternal and paternal Holocaust exposure or associated with both maternal and paternal age at Holocaust exposure were in the same direction. Moreover, the DEGs associated with parental Holocaust exposure were enriched for glucocorticoid-regulated genes and immune pathways with some of these genes mediating the effects of parental Holocaust exposure on C-reactive protein. The top gene across all analyses was MMP8, encoding the matrix metalloproteinase 8, which is a regulator of innate immunity. To conclude, this study identified a set of glucocorticoid and immune-related genes in association with parental Holocaust exposure with differential effects based on parental exposure-related factors.