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Background: Perceived adverse effects of antimalarial chemoprophylaxis can be difficult to distinguish from travel-related illness and are often cited as important reasons for non-adherence or refusal of antimalarial chemoprophylaxis. We aimed to investigate the occurrence of symptoms of illness in travellers with and without chemoprophylaxis in a cross-sectional study after travel and to identify risk factors for non-adherence to prophylaxis., Methods: We enrolled 458 travellers to Africa and South America during their pre-travel medical consultation at the travel clinic of the University Medical Centre Hamburg-Eppendorf and conducted post-travel interviews on symptoms of illness and intake of malaria prophylaxis., Results: Eleven percent (49/437) of the participants reported symptoms of illness during travel. In total, 36% (160/448) of the participants reported prescription of chemoprophylaxis, the vast majority of these travelled to Africa (98%) and received atovaquone/proguanil (93%). Frequency of symptoms did not differ significantly between participants without prophylaxis and those taking atovaquone/proguanil. Non-adherence to prophylaxis was frequent (20%), but only 3% (4/149) of the participants stopped the medication early because of perceived side effects. Risk factors associated with non-adherence to prophylaxis included age under 30 years, travel to West or Central Africa and travel duration greater than 14 days., Conclusions: Symptoms of illness during travel occurred at similar frequencies irrespective of intake of chemoprophylaxis. Travellers should be informed about chemoprophylaxis in a balanced way, without raising fear of side effects, especially among groups at higher risk for incorrect use of prophylaxis., (© International Society of Travel Medicine 2023. Published by Oxford University Press.)