Every season, circulating influenza viruses change; therefore, vaccines must be reformulated each year. We aimed to estimate vaccine effectiveness (VE) against severe influenza infection for the 2018/19 season in Italy. We conducted a test-negative design case-control study at five Italian hospitals. We estimated influenza VE against severe acute respiratory infection (SARI) requiring hospitalisation overall, and by virus subtype, vaccine brand, and age. The 2018/19 season was characterised by A(H1N1)pmd09 and A(H3N2) influenza viruses. Vaccine coverage among <18 years recruited SARI cases was very low (3.2%). Seasonal vaccines were moderately effective against type A influenza overall (adjusted VE = 40.5%; 95% confidence interval (CI) = 18.7–56.4%) and subtype A(H1N1)pmd09 viruses (adjusted VE = 55%; 95% CI = 34.5–69.1%), but ineffective against subtype A(H3N2) viruses (adjusted VE = 2.5%; 95% CI = −50.0–36.7%). Both Fluad and Fluarix Tetra vaccines were effective against type A influenza overall and subtype A(H1N1)pdm09 viruses. VE appeared to be similar across age groups (0–64 years, ≥65 years). Seasonal influenza vaccines in the 2018/19 season were moderately effective in preventing SARI caused by A(H1N1)pdm09 influenza but ineffective against A(H3N2).