Background <p>The choice of a specific anatomic site for vaccine administration may influence rates of acceptance but has not been studied before.</p> Methods <p>We conducted a randomized controlled trial in a pretravel clinic, comparing reported levels of satisfaction and pain on a scale of 0 to 10, and the frequency of adverse events (AEs) for vaccination in different anatomic sites. Travelers receiving one vaccine were randomized to be immunized in the deltoid or the vastus lateralis muscle. Travelers receiving multiple vaccines were randomized to be immunized in both the vastus lateralis and deltoid muscles or preferably in either the deltoid or the vastus lateralis muscles.</p> Results <p>For the 159 participants receiving multiple vaccines day 0 and day 7 satisfaction levels for the vastus lateralis, combined strategy or the deltoid injection sites were 9.00 ± 1.63, 9.46 ± 1.16 and 9.82 ± 0.52 (<i>p</i> = 0.001), and 6.62 ± 3.16, 8.87 ± 1.91 and 8.87 ± 2.05 (<i>p</i> &lt; 0.001), respectively. For the 33 participants who received a single vaccine, day 0 and day 7 satisfaction levels for the vastus lateralis and deltoid muscles were 8.9 ± 2.2 and 10 ± 0.0 (<i>p</i> = 0.048) and 7.8 ± 2.7 and 9.8 ± 0.5 (<i>p</i> = 0.04), respectively. Pain levels on day 0 were similar across all study groups. However, muscle pain on day 7 was reported more frequently among participants vaccinated in the thigh region (61.7%) compared to those vaccinated in the deltoid muscle (31.9%) or at both sites (43.8%) (<i>p</i> &lt; 0.01). Additionally, localized adverse events were reported more often by females (74.2%) than by males (48.8%) (<i>p</i> = 0.002).</p> Conclusions <p>We found lower levels of satisfaction in travelers vaccinated in the thigh region. Such data may aid in increasing vaccination coverage and may influence practice guidelines.</p> Trial registration <p>The trial was registered in accordance with local regulatory requirements under study identification number RMB518-18.</p>