Background. Older adults are at increased risk of influenza-associated complications, including hospitalization, but influenza vaccine effectiveness (VE) data are limited for this population. We conducted a case-control study to estimate VE to prevent laboratory- confirmed influenza hospitalizations among adults aged ≥50 years in 11 US Emerging Infections Program hospitalization surveillance sites. Methods. Cases were influenza infections (confirmed by reverse-transcription polymerase chain reaction) in adults aged ≥50 years hospitalized during the 2010-2011 influenza season, identified through Emerging Infections Program surveillance. Community controls, identified through home telephone lists, were matched by age group (±5 years), county, and month of hospitalization for case patients. Vaccination status was determined by self-report (with location and date) or medical records. Conditional logistic regression models were used to calculate adjusted VE (aVE) estimates (100 × [1 - adjusted odds ratio]), adjusting for sex, race, socioeconomic factors, smoking, chronic medical conditions, recent hospitalization for a respiratory condition, and functional status. Results. Among case patients, 205 of 368 (55%) were vaccinated, compared with 489 of 773 controls (63%). Case patients were more likely to be of nonwhite race and more likely to have ≥2 chronic health conditions, a recent hospitalization for a respiratory condition, an income <$35 000, and a lower functional status score (P < .01 for all). The aVE was 56.8% (95% confidence interval, 34.1%-71.7%) and was similar across age groups, including adults ≥75 years (aVE, 57.3%; 15.9%-78.4%). Conclusions. During 2010-2011, influenza vaccination was associated with a significant reduction in the risk of laboratoryconfirmed influenza hospitalization among adults aged ≥50 years, regardless of age group. [ABSTRACT FROM AUTHOR]