The study investigates the impact of smoking on immune responses and identifies smoking, cytomegalovirus (CMV) latent infection, and body mass index (BMI) as major contributors to variability in cytokine secretion. Smoking influences both innate and adaptive immune responses, with its effects on innate responses quickly disappearing after quitting and its effects on adaptive responses persisting long-term. The persistence of smoking's effects on adaptive responses is associated with epigenetic memory, specifically DNA methylation at signal trans-activators and regulators of metabolism. The study also identifies 136 variables associated with cytokine secretion variability, including genetic factors, and highlights the clinical implications of these findings for the risk of infections, cancers, and autoimmune diseases. The results provide new insights into the mechanisms underlying immune response variability and the role of modifiable environmental factors.The study investigates the impact of smoking on immune responses and identifies smoking, cytomegalovirus (CMV) latent infection, and body mass index (BMI) as major contributors to variability in cytokine secretion. Smoking influences both innate and adaptive immune responses, with its effects on innate responses quickly disappearing after quitting and its effects on adaptive responses persisting long-term. The persistence of smoking's effects on adaptive responses is associated with epigenetic memory, specifically DNA methylation at signal trans-activators and regulators of metabolism. The study also identifies 136 variables associated with cytokine secretion variability, including genetic factors, and highlights the clinical implications of these findings for the risk of infections, cancers, and autoimmune diseases. The results provide new insights into the mechanisms underlying immune response variability and the role of modifiable environmental factors.