Background: Neurocognitive dysfunction is reported in women with breast cancer even prior to receipt of adjuvant therapy; however, there is little understanding of underlying mechanisms. We tested the hypothesis that pretreatment neurocognitive dysfunction in newly diagnosed patients is related to immunological activation, as indexed by pro-inflammatory cytokines. Methods: One hundred seventy-four postmenopausal patients with newly diagnosed breast cancer underwent a comprehensive neuropsychological evaluation (assessment of cognitive function, mood, and fatigue) and measurement of key cytokine levels prior to surgery. Age-matched control participants without cancer were evaluated concurrently. Multivariable regression analyses examined the contribution of circulating Interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and soluble TNF receptor type two (sTNF-RII) in predicting neurocognitive performance in patients after controlling for key factors thought to impact functioning. All tests of statistical significance were two-sided. Results: Memory performance was statistically significantly reduced, in patients compared with controls (P =. 02). Of the three cytokines measured, only IL-1ra was statistically significantly elevated in cancer patients when compared with control participants (mean ± SD, 375 ± 239 pg/mL vs 291 ± 169 pg/mL, P =. 007). After controlling for age, education, race, mood, fatigue, body mass index, and comorbidity, cytokines independently explained 6.0% of the total variance in memory performance (P =. 01) in cancer patients but not control participants, with higher sTNF-RII associated with worse functioning. Exploratory analyses found that comorbidity statistically significantly explained variance in processing speed and executive functioning (P =. 03 and P =. 03, respectively). Conclusion: An association of TNF with memory, previously reported in patients after exposure to chemotherapy, was found prior to initiation of any treatment, including surgery. This association requires further investigation as sTNF-RII was not higher in cancer patients relative to control participants.