Increasing use of immunosuppressive biologic therapies poses a challenge for infectious diseases. Immunosuppressed patients have a high risk for influenza complications and an impaired immune response to vaccines. The total burden of immunosuppressive conditions in the United States, including those receiving emerging biologic therapies, remains unknown. We used the national claims database MarketScan to estimate the prevalence of immunosuppressive conditions and risk for acute respiratory illnesses (ARIs). We studied 47.2 million unique enrollees, representing 115 million person-years of observation during 2012-2017, and identified immunosuppressive conditions in 6.2% adults 18-64 years of age and 2.6% of children <18 years of age. Among 542,105 ARI hospitalizations, 32% of patients had immunosuppressive conditions. The risk for ARI hospitalizations was higher among enrollees with immunosuppression than among nonimmunosuppressed enrollees. Future efforts should focus on developing improved strategies, including vaccines, for preventing influenza in immunosuppressed patients, who are an increasing population in the United States.