The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n D 15) and non-fatigued (n D 12) diseasefree cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and postvaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre-and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 § 1201 counts), and a trend in a similar direction with strain H1N1 (3025 § 2339 counts), compared to non-fatigued patients (3099 § 2401 and 5877 § 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 § 2.1% versus 2.4 § 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 § 44.3 pg/ml vs. 94.0 § 45.4 pg/ml with strain H3N2 and 28.4 § 44.0 pg/ml versus 74.5 § 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, postvaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation.