Programmed death-ligand 1 (PD-L1) can reduce the immune response by inhibiting CD8 T-cell proliferation and cytotoxic activity. We studied a series of human viral (molloscum, human papillomavirus, herpes simplex, cytomegalovirus, Epstein-Barr virus, smallpox) and bacterial infections (Helicobacter pylori) for the in situ expression of PD-L1, mononuclear cell infiltration, and CD8 activity and compared this to noninfectious idiopathic inflammatory conditions to better define which immune responses may be more highly correlated with an infectious agent. Each viral and bacterial infection showed an increased PD-L1 expression that was most prominent in the mononuclear cell/CD8+ infiltrate surrounding the infection. However, the CD8 cells were mostly quiescent as evidenced by the low Ki67 index and minimal granzyme expression. Using a melanoma mouse model, acute reovirus infection increased PD-L1 expression, but decreased CD8 cytotoxic activity and Treg (FOXP3) cell numbers. In comparison, idiopathic noninfectious chronic inflammatory processes including lichen sclerosis, eczema, Sjogren's disease, and ulcerative colitis showed a comparable strong PD-L1 expression in the mononuclear cell infiltrates but much greater Treg infiltration. However, this strong immunosuppressor profile was ineffective as evidenced by strong CD8 proliferation and granzyme expression. These data suggest that viral and bacterial infections induce a PD-L1 response that, unlike noninfectious chronic inflammatory conditions, dampens the activity of the recruited CD8 cells which, in turn, may enhance the ability of anti-PD-L1 therapy to eliminate the infectious agent.