Cytokines play important roles in B-cell activation, proliferation, and apoptosis, thus may be etiologically related to risk of B-cell non-Hodgkin lymphoma (B-NHL). However, the association between circulating levels of cytokines and B-NHL risk has not been prospectively studied in non-HIV populations. The objective of this study was to assess this association by conducting a case-control study nested within a prospective cohort of non-HIV-infected, healthy women. Fifteen cytokines were measured in samples collected a median of 8.2 years prior to diagnosis in 92 cases and two matched controls per case. Only cytokines that showed adequate temporal reproducibility over a two-year period were included. The odds ratio (OR) for the highest tertile relative to the lowest was elevated for soluble IL-2 receptor (sIL-2R) (OR = 2.5, 95% CI = 1.4-4.7, p (trend) < 0.01) and decreased for IL-13 (OR = 0.5, 95% CI = 0.2-1.0, p (trend) = 0.05). Three other cytokines were marginally associated with risk of B-NHL: TNF-alpha (OR = 1.7, 95% CI = 0.9-3.3, p (trend) = 0.11), sTNF-R2 (OR = 1.9, 95% CI = 0.9-3.5, p (trend) = 0.06), and IL-5 (OR = 0.5, 95% CI = 0.3-1.0, p (trend) = 0.06). No association was observed between B-NHL risk and levels of the other cytokines measured (IL-1beta, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, IL-12p70, CRP and sTNF-R1). This study suggests that dysregulated cytokines may be involved in B-NHL development.