Although severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), it is unclear whether subclinical immune system function influences lymphomagenesis. To address this question, we conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to investigate whether circulating levels of cytokines and other immune markers are associated with future risk of NHL. Selected cytokines [interleukin (IL)-4, IL-6, IL-10, and TNF-α] and other immune markers [soluble TNF receptor 1 (sTNF-R1), sTNF-R2, C-reactive protein, and sCD27] were measured in prediagnostic serum specimens from 297 incident NHL cases and 297 individually matched controls. ORs and 95% confidence intervals (CI) relating quartiles of analyte concentration to NHL risk were calculated by using conditional logistic regression. Statistically significant associations with increased NHL risk were observed for elevated serum levels of sTNF-R1 (quartile 4 vs. quartile 1: OR = 1.7, 95% CI: 1.1-2.8; P(trend) = 0.02) and sCD27 (OR = 5.3, 95% CI: 2.9-9.4; P(trend) < 0.0001). These associations remained in analyses of cases diagnosed longer than 6 years following blood collection (sTNF-R1: OR = 2.1, 95% CI: 1.0-4.0, P(trend) = 0.01; sCD27: OR = 4.1, 95% CI: 1.9-8.5, P(trend) = 0.0001). Elevated levels of IL-10, TNF-α and sTNF-R2 were also significantly associated with increased risk of NHL overall; however, these associations weakened with increasing time from blood collection to case diagnosis and were null for cases diagnosed longer than 6 years postcollection. Our findings for sTNF-R1 and sCD27, possible markers for inflammatory and B-cell stimulatory states, respectively, support a role for subclinical inflammation and chronic B-cell stimulation in lymphomagenesis.