BACKGROUND Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with profound disease‐related cellular, humoral, and innate immune suppression. The objective of this study was to study the correlations between stress and disease‐specific, negative prognostic cellular, cytokine, and chemokine markers in patients with CLL. METHODS A single‐group, observational design was used. Patients with relapsed/refractory CLL (N = 96) who were entering a phase 2 trial of an experimental therapy (ibrutinib) were studied. Before the first dose, a validated self‐report measure of stress (the Impact of Event Scale) was completed, and blood was drawn for absolute lymphocyte counts (ALCs) and for cytokine and chemokine enzyme‐linked immunosorbent assays. Multiple linear regression models tested stress as a concurrent predictor of ALCs; of cytokines (tumor necrosis factor α TNFα, a proliferation‐inducing ligand APRIL, B‐cell activating factor BAFF, interleukin 6 IL‐6, IL‐10, IL‐16, and vascular endothelial growth factor VEGF); and of the chemokine (C‐C motif) ligand 3 (CCL3). RESULTS Controlling for relevant demographic variables, comorbidities, CLL genetic risk (deletion of the short arm of chromosome 17 del17p), and correlates of inflammation, stress predicted higher ALCs (P < .05), and higher levels of TNFα (P < .05), IL‐16 (P < .01), and CCL3 (P < .05). Stress was not associated with APRIL, BAFF, IL‐6, IL‐10, or VEGF. CONCLUSIONS Novel biobehavioral data from patients with relapsed/refractory CLL demonstrate that stress is related to heightened levels of cellular, cytokine, and chemokine markers associated previously with progressive disease in CLL. The current results indicate that stress is related to immune and inflammatory processes that contribute to cancer cell proliferation and survival. These data provide a first look into these processes. Cancer 2018. © 2018 American Cancer Society. Stress predicts heightened levels of cellular, cytokine, and chemokine markers in patients with chronic lymphocytic leukemia. Psychological stress is related to cellular, cytokine, and chemokine markers associated with progressive disease in chronic lymphocytic leukemia.