© The Royal Australian and New Zealand College of Psychiatrists. Objective: Immune alterations may play a role in bipolar disorder etiology; however, the relationship between overall immune system functioning and mood symptom severity is unknown. Methods: The two comparative effectiveness trials, the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study (Bipolar CHOICE) and the Lithium Treatment Moderate-Dose Use Study (LiTMUS), were similar trials among patients with bipolar disorder. At study entry, white blood cell count and bipolar mood symptom severity (via Montgomery-Aasberg Depression Rating Scale and Bipolar Inventory of Symptoms Scale) were assessed. We performed analysis of variance and linear regression analyses to investigate relationships between deviations from median white blood cell and multinomial regression analysis between higher and lower white blood cell levels. All analyses were adjusted for age, gender, body mass index, smoking, diabetes, hypertension and hyperlipidemia. Results: Among 482 Bipolar CHOICE participants, for each 1.0 × 109/L white blood cell deviation, the overall Bipolar Inventory of Symptoms Scale severity increased significantly among men (coefficient = 2.13; 95% confidence interval = [0.46, '3.79]; p = 0.013), but not among women (coefficient = 0.87; 95% confidence interval = ['0.87, '2.61]; p = 0.33). Interaction analyses showed a trend toward greater Bipolar Inventory of Symptoms Scale symptom severity among men (coefficient = 1.51; 95% confidence interval = ['0.81, '3.82]; p = 0.2). Among 283 LiTMUS participants, higher deviation from the median white blood cell showed a trend toward higher Montgomery-Aasberg Depression Rating Scale scores among men (coefficient = 1.33; 95% confidence interval = ['0.22, '2.89]; p = 0.09), but not among women (coefficient = 0.34; 95% confidence interval = ['0.64, '1.32]; p = 0.50). When combining LiTMUS and Bipolar CHOICE, Montgomery-Aasberg Depression Rating Scale scores increased significantly among men (coefficient = 1.09; 95% confidence interval = [0.31, '1.87]; p = 0.006) for each 1.0 × 109/L white blood cell deviation, whereas we found a weak association among women (coefficient = 0.55; 95% confidence interval = ['0.20, '1.29]; p = 0.14). Lower and higher white blood cell levels correlated with greater symptom severity and specific symptoms, varying according to gender. Conclusion: Deviations in an overall immune system marker, even within the normal white blood cell range, correlated with mood symptom severity in bipolar disorder, mostly among males. Studies are warranted investigating whether white blood cell count may predict response to mood-stabilizing treatment.