Background: Since the beginning of the pandemic, five variants of epidemiological interest have been identified, each of them with its pattern of symptomology and disease severity. The aim of this study is to analyze the role of vaccination status in modulating the pattern of symptomatology associated with COVID-19 infection during four waves. Methods: Data from the surveillance activity of healthcare workers were used to carry out descriptive analysis, association analyses and multivariable analysis. A synergism analysis between vaccination status and symptomatology during the waves was performed. Results: Females were found at a higher risk of developing symptoms. Four SARS-CoV-2 waves were identified. Pharyngitis and rhinitis were more frequent during the fourth wave and among vaccinated subjects while cough, fever, flu syndrome, headache, anosmia, ageusia, arthralgia/arthritis and myalgia were more frequent during the first three waves and among unvaccinated subjects. A correlation was found between vaccination and the different waves in terms of developing pharyngitis and rhinitis. Conclusion: Vaccination status and viruses’ mutations had a synergic effect in the mitigation of the symptomatology caused by SARS-CoV-2 in healthcare workers.