This chapter presents a comprehensive examination of the relationship between vaccination status and Long COVID fatigue, analyzing both pre- and post-infection vaccination effects through extensive research data. Drawing from multiple large-scale studies, including a UK-based analysis of 1.2 million adults and a US cohort study of 240,648 patients, the chapter demonstrates that pre-infection vaccination significantly reduces the risk of developing Long COVID fatigue. The text provides detailed analysis of vaccine types, with particular attention to comparative effectiveness between mRNA vaccines (Pfizer-BioNTech and Moderna) and adenoviral vector vaccines (AstraZeneca), revealing superior outcomes for mRNA platforms. The chapter explores mechanistic insights into how vaccines may influence fatigue symptoms, including immunological responses and viral persistence. Clinical implications are thoroughly discussed, offering guidance for healthcare providers on risk assessment, patient education, and treatment planning. The chapter concludes with an evidence-based examination of vaccine safety, specifically addressing and debunking the myth of vaccination’s link to autism spectrum disorders through comprehensive research data. Throughout, the text emphasizes the importance of timing in vaccination effectiveness and the need for individualized patient care approaches.