General vaccination rates have been falling globally despite unequivocal health benefits. Noncompliance can result from access barriers and/or hesitant attitudes. Few studies have investigated the prevalence and determinants of noncompliance with COVID-19 vaccination in blood donors. We surveyed blood donors on COVID-19 infection and vaccination history, barriers and motivations for COVID-19 vaccination, and comorbidities. We estimate the prevalence of noncompliance, the prevalence of hesitancy toward COVID-19 vaccines, and investigate associated factors using multivariable models. From December 2021 to December 2022, 33,610 survey respondents were included. Of these, 24% had not been vaccinated for COVID-19 or had missing vaccination information, and 99% of those who reported reasons for being unvaccinated declared at least one of three hesitant attitudes presented in the survey (safety concerns; personal/cultural/religious beliefs; being young and not worrying about being vaccinated). Among noncompliant donors, <2% reported access barriers. In the multivariable model addressing factors associated with vaccine noncompliance, younger age, male gender, White/Caucasian race, absence of comorbidities, residency in a State with less restrictive COVID-19 policies, and living in micropolitan or rural areas were identified as significant predictors. Younger age and White/Caucasian race were independently associated with vaccine hesitancy among noncompliant donors. We found high rates of noncompliance with COVID-19 vaccination in blood donors, mostly driven by vaccine hesitancy. Understanding vaccine adherence among blood donors-a relatively highly educated and healthy population, with good healthcare access and usually motivated by altruism-could provide key information on determinants of vaccine noncompliance that may be harder to overcome.