The effectiveness of influenza vaccines against a variety of serious diseases, including critical illness and death, is still unknown. During the 2019–2020 season, which was marked by the circulation of drifted A/H1N1 and B-lineage viruses, the researchers conducted a test-negative trial in an intensive care unit (ICU) network of ten US hospitals to investigate VE for preventing influenza-associated severe acute respiratory infection (SARI). Adults with laboratory-confirmed, influenza-associated SARI were hospitalized in the ICU and a specified number outside the ICU (to capture a spectrum of severity). The frequency of test-negative controls was matched by the hospital, admission date, and care location (ICU vs. non-ICU). Age, comorbidities, and other confounders were all considered in the calculations. The median (interquartile) age of the 638 patients was 57 (44–68); 286 (44.8%) of the patients were treated in the ICU, and 42 (6.6%) died during their stay. Vaccination was given to 45% of patients and 61% of controls, resulting in a VE of 32% (95% CI: 2–53%), with 28% (9% to 52%) against influenza A and 52% (13–74%) against influenza B. Adults aged 18–49 (62%; 95% CI: 27–81%) had higher VE than those aged 50–64 (20%; 48% to 57%) and more than or more than or equal to 65 (3%; 95% CI: 97% to 46%) (P=.0789 for interaction). VE was found to be much more effective than nonfatal influenza sickness in preventing influenza-related death (80%; 95% CI: 4–96%). Vaccination reduced severe influenza-associated disease among adults by 32% during a season with dispersed viruses. Young adults have a high level of VE.