OBJECTIVES: An unmet need remains for new effective treatments and/or management strategies for influenza in high-risk groups. Complications and mortality rates might differ among high risk groups, such as those who are aged 65 years and older compared with those with different chronic underlying medical conditions. METHODS: A literature review was performed using electronic database keyword searches, specific inclusion and exclusion criteria, quality rating of the reviewed full-text articles, and abstraction of data to evaluate the published evidence on the incidence, complication rates, and health service use associated with clinical influenza in different high-risk groups. RESULTS: Key findings for incidence rates of clinical influenza were that these rates are similar among people with chronic cardiovascular or respiratory comorbidity but may be higher in those with allogeneic stem cell transplants compared to those with autologous transplants. Rates of hospitalization and/or pneumonia or lower respiratory tract infection for those with chronic conditions or those who are immunocompromised (2.9% to 80%) are significantly higher than those in people over age 65 but without additional high-risk factors (0%). A person who is hospitalized and has a laboratory-confirmed influenza diagnosis has a probability of intensive care unit admission of between 11.8% and 28.6% and of death of between 2.9% and 14.3%. Most of the studies of hospitalized patients did not present outcomes data separately by high-risk group. In addition, the rates and outcomes of influenza complications in all high-risk groups are variable from year to year depending on the circulating influenza viruses. CONCLUSIONS: These findings indicate that the burden of influenza may vary by high-risk group although there are only limited data available to quantify these differences. This information could be used to evaluate new therapies, including better influenza vaccines, chemoprophylaxis, and/or treatment strategies for different high-risk groups.