Influenza remains a major source of morbidity and increased mortality among patients with cancer, and prior studies had indicated impaired response to vaccination. In the current report, lymphoma patients treated with rituximab, either in combination with chemotherapy or as a single agent, were found to have markedly deficient influenza vaccine response, with not 1 of 67 achieving a protective titer, compared with 42 of 51 controls. Thus, rituximab-treated lymphoma patients are particularly susceptible to vaccine failure and influenza infection should be highly considered in symptomatic patients, even in those who had been appropriately vaccinated.