BACKGROUND: Influenza A viruses are a major cause of viral respiratory infections in humans, leading to a spectrum of diseases ranging from mild to severe, particularly in high-risk groups. Monitoring the frequency and evolution of A (H1N1)pdm09 viruses is essential for guiding vaccine strain selection and maintaining vaccine effectiveness. OBJECTIVES: To characterize the evolution of circulating influenza A (H1N1)pdm09 strains in Mar del Plata(MDQ), Argentina, and estimate vaccine efficacy from 2015 to 2020, before the SARS-CoV-2 pandemic. METHODS: We analyzed 46 influenza A (H1N1)pdm09 strains detected by RT-PCR from patients with acute respiratory infections in MDQ between 2015 and 2020. Phylogenetic analysis was performed using maximum likelihood, and vaccine efficacy was estimated with the P RESULTS: Seven genetic clades were identified: 6B in 2015, 6B.1 in 2016-2017, 6B.1A, 6B.1A.1, and 6B.1A.3 in 2018, 6B.1A.5A in 2019-2020, and 6B.1A.5a.2 in 2020. Genetic diversity and regional clustering suggested multiple strain introductions from other Argentinian regions or countries. The predicted vaccine efficacy was highest when the frequency of influenza A (H1N1)pmd09 was below 2%, decreasing as viral frequency increased, due to mutations occurring particularly in haemagglutinin epitopes B, C, and E. CONCLUSION: Our findings highlight the dynamic evolution of influenza A (H1N1)pdm09 in MDQ and emphasize the importance of continuous molecular surveillance and regular vaccine updates. Additionally, the P