Little is known about cell-mediated immune responses to natural influenza infection in solid organ transplant (SOT) patients. The aim of our study was to evaluate the CD4⁺ and CD8⁺ responses to influenza A and B infection in a cohort of SOT patients. We collected peripheral blood mononuclear cells at influenza diagnosis and four weeks later from 31 SOT patients during the 2017–2018 influenza season. Infection-elicited influenza-specific CD4⁺ and CD8⁺ T-cell responses were measured using flow cytometry and intracellular cytokine staining and compared to responses following influenza vaccine in SOT patients. Natural infection was associated with a significant increase in CD4⁺ T-cell responses. For example, polyfunctional cells increased from 21 to 782 and from 193 to 1436 cells per 10⁶ CD4⁺ T-cells among influenza A/H3N2 and B-infected patients (p = 0.006 and 0.004 respectively). Moreover, infection-elicited CD4⁺ responses were superior than vaccine-elicited responses for influenza A/H1N1 (931 vs 1; p = 0.026), A/H3N2 (647 vs 1; p = 0.041) and B (619 vs 1; p = 0.004). Natural influenza infection triggers a significant increase in CD4⁺ T-cell responses in SOT patients. Infection elicits significantly stronger CD4⁺ responses compared to the influenza vaccine and thereby likely elicits better protection against reinfection.