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Background: Vaccine hesitancy is an important public health problem as it could prolong the pandemic. Aim: To assess moderating effect of psychological antecedents and conspiracy mentality on COVID-19 vaccine hesitancy in a sample of Egyptians. Design: Cross-sectional research design was adopted during COVID-19 outbreak. Sample: Convenience sample of 1390 participants was recruited through a web-based survey. Tools: Four tools used for data collection: Demographic and Medical Data Sheet, Oxford COVID-19 Vaccine Hesitancy Scale, Conspiracy Mentality Scale, and 5 Cs Psychological Antecedents of Vaccination Scale. Results: About 45.3% reported vaccine hesitancy that was highly significantly correlated to conspiracy beliefs. Confidence, complacency, constraints and responsibility appeared as major psychological factors that separates the vaccine acceptance group from the hesitancy group. Social media was the main source of information about COVID-19 vaccine. About (59.2% & 38.5%) had moderate and high conspiracy mentality respectively. Conclusion: Psychological factors and conspiracy beliefs impacted vaccine hesitancy among participants. Recommendations: Educational programs should be implemented to increase the awareness of the safety and efficacy of COVID-19 vaccines.