Abstract: BACKGROUND: Post-viral secondary bacterial infections, such as those caused by Streptococcus pneumoniae, are strongly associated with influenza and respiratory syncytial virus (RSV). However, data evaluating this relationship with coronavirus disease 2019 (COVID-19) are limited. METHODS: A retrospective analysis was conducted in hospitalized patients in Veterans Affairs (VA) hospitals across the United States from 1 January 2015 to 1 March 2025 to determine the risk of secondary S pneumoniae infection after respiratory viral disease. The primary outcome was development of S pneumoniae infection within 30 days after a positive test for influenza, RSV, or COVID-19. RESULTS: In total, 188 721 hospitalized patients who received care at a VA hospital were tested for a viral respiratory infection. Of those, 8165 were positive for S pneumoniae after respiratory viral testing. Both influenza and RSV infections were associated with increased odds of S pneumoniae infection (odds ratio [OR]: 2.39 [95% CI: 2.15-2.64] and 2.50 [95% CI: 2.07-2.99], respectively). However, prior COVID-19 infection decreased the odds of S pneumoniae infection (OR: .56; 95% CI: .50-.62). Additionally, current smokers and those with chronic obstructive pulmonary disease were also associated with increased odds of subsequent S pneumoniae (OR: 1.09 [95% CI: 1.03-1.16] and 1.36 [95% CI: 1.28-1.45], respectively). CONCLUSIONS: Study results demonstrated that influenza and RSV are associated with a higher risk of post-viral secondary S pneumoniae infection, while COVID-19 did not appear to increase such risk.