To review the efficacy and safety of the high-dose inactivated influenza vaccine quadrivalent (HD-IIV4) in the prevention of influenza in older adults. A literature search was performed using PubMed and Google Scholar with the search terms high-dose, influenza vaccine, and quadrivalent. Other resources included the Centers for Disease Control and Prevention (CDC), the prescribing information, and the manufacturer's website. All relevant English-language articles of studies assessing the efficacy and safety of HD-IIV4 were included. HD-IIV4 is licensed by the Food and Drug Administration for the prevention of influenza in adults aged 65 years and older. The safety and immunogenicity of HD-IIV4 was demonstrated in a phase 3 trial, and the efficacy of the trivalent formulation (HD-IIV3) was demonstrated in a phase 3b-4 trial. HD-IIV4 carries a warning regarding the occurrence of Guillain-Barré syndrome. Adverse reactions, including injection-site pain and myalgia, were reported more frequently with HD-IIV4 than with HD-IIV3. Although the CDC recommends any age-appropriate influenza vaccine for adults aged 65 years and older, HD-IIV4 was associated with improved immunogenicity against the added B strain and HD-IIV3 provided better protection against influenza than the standard-dose vaccine. Other influenza vaccines have weaker evidence of efficacy in older adults. Therefore, HDIIV4 should be recommended as the vaccine of choice in adults aged 65 years and older. HD-IIV4 has proven immunogenic, safe, and effective in preventing influenza in older adults and should be recommended as the vaccine of choice in this patient population.