Recent research shows bidirectional communication between the normal brain and the peripheral immune system. Glioma is a primary brain tumor characterized by systemic immunosuppression. To better understand gliomagenesis, we evaluated associations between 277 prediagnostic serum cytokines and glioma. We used glioma (n = 487) and matched control (n = 487) specimens from the Janus Serum Bank Cohort in Oslo, Norway. Conditional logistic regression allowed us to identify those cytokines that were individually associated with glioma. Next, we used heat maps to compare case to control Pearson correlation matrices of 12 cytokines modeled in an in silico study of the interaction between the microenvironment and the tumor. We did the same for case-control correlation matrices of lasso-selected cytokines and all 277 cytokines in the data set. Cytokines related to glioma risk (P ≤ .05) more than 10 years before diagnosis are sIL10RB, VEGF, beta-Catenin and CCL22. LIF was associated with decreased glioma risk within five years before glioma diagnosis (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23, 0.94). After adjustment for cytokines above, the previously observed interaction between IL4 and sIL4RA persisted (> 20 years before diagnosis, OR = 1.72, 95% CI = 1.20, 2.47). In addition, during this period, case correlations among 12 cytokines were weaker than were those among controls. This pattern was also observed among 30 lasso- selected cytokines and all 277 cytokines. We identified four cytokines and one interaction term that were independently related to glioma risk. We have documented prediagnostic changes in serum cytokine levels that may reflect the presence of a preclinical tumor.