Introduction - Against the backdrop of the global COVID-19 pandemic and the concerning spread of the more transmissible 20J/501Y.V3 (P1) variant, an mRNA vaccine became available in French Guiana starting in mid-January 2021. This study aimed to assess vaccination intentions among healthcare professionals in French Guiana. Methods - A cross-sectional survey was conducted from January 22 to March 26, 2021, among a sample of healthcare workers in French Guiana using a widely distributed anonymous online questionnaire. Results - A total of 579 healthcare professionals agreed to participate in this study, including 220 physicians and 200 nurses, most of whom worked in hospitals (54%) or in private practice (22%). Overall, 65.6% of respondents stated that they wanted to get vaccinated or had already been vaccinated against COVID-19, while 24.3% of respondents stated that they did not want to get vaccinated against COVID-19 and 11.2% were uncertain. In multivariate analysis, factors associated with a greater intention to get vaccinated were older age, level of concern regarding COVID-19, trust in information provided about vaccines, and having been vaccinated against the flu the previous year. Conversely, reluctance toward certain vaccinations in general (ORa=0.23, 95% CI: [0.13–0.41]) and being from the Antilles or French Guiana (0.39 [0.21–0.73]) were associated with greater distrust of vaccination. Conclusion—Negative views and attitudes toward vaccines are a major public health concern among healthcare professionals in French Guiana. Regional specificities, general vaccine hesitancy, and concerns about future side effects in particular represent significant barriers and/or factors. Low trust in the government and science is a significant factor in the refusal of the COVID-19 vaccine among non-medical staff. Public health messages containing information on vaccine safety should be tailored to address these concerns.