Inflammation and B-cell hyperactivation have been associated with non-Hodgkin 
lymphoma development. This prospective analysis aimed to further elucidate 
pre-diagnosis plasma immune marker profiles associated with non-Hodgkin lymphoma 
risk. We identified 598 incident lymphoma cases and 601 matched controls in 
Nurses' Health Study and Health Professionals Follow-up Study participants with 
archived pre-diagnosis plasma samples and measured 13 immune marker levels with 
multiplexed immunoassays. Using multivariable logistic regression we calculated 
Odds Ratios (OR) and 95% Confidence Intervals (CI) per standard deviation unit 
increase in biomarker concentration for risk of non-Hodgkin lymphoma and major 
histological subtype, stratifying additional models by years (<5, 5 to <10, ≥10) 
after blood draw. Soluble interleukin-2 receptor-α, CXC chemokine ligand 13, 
soluble CD30, and soluble tumor necrosis factor receptor-2 were individually 
positively associated, and B-cell activating factor of the tumor necrosis factor 
family inversely associated, with all non-Hodgkin lymphoma and one or more 
subtypes. The biomarker combinations associated independently with lymphoma 
varied somewhat by subtype and years after blood draw. Of note, the unexpected 
inverse association between B-cell activating factor and chronic lymphocytic 
leukemia/small lymphocytic lymphoma risk (OR: 95%CI: 0.51, 0.43-0.62) persisted 
more than ten years after blood draw (OR: 0.70; 95%CI: 0.52-0.93). In 
conclusion, immune activation precedes non-Hodgkin lymphoma diagnosis by several 
years. Decreased B-cell activating factor levels may denote nascent chronic 
lymphocytic leukemia many years pre-diagnosis.