To evaluate the factors affecting personal protective equipment (PPE) associated with headaches in healthcare workers during the first hit of coronavirus disease 2019 (COVID-19) outbreak in China in order to provide evidence for improving the prevention and treatment of PPE-associated headaches in frontline medical personnel.In this cross-sectional study, the baseline characteristics and the prevalence of the PPE-associated headaches among frontline healthcare workers at Wuhan Taikang Hospital were objectively evaluated by means of a questionnaire survey. We obtained predictors of PPE-associated headaches frequency by multiple regression analyses. The path analysis model was applied to determine the interrelationships between the variables related to PPE-associated headaches frequency.Among the 520 participants, 436 (83.85 %) reported PPE-associated headaches during the anti-epidemic period. Compare with non-PPE-associated headache, age, PHQ-9 score >10, nurses, and PSQI>5were statistically significant found in participants with PPE-associated headaches. Multivariable linear regression showed that the occupation(nurse), pre-existing primary headache diagnosis, headache intensity and depression were risk factors for the frequency of PPE-associated headaches. The path analysis model observed that direct effects from occupation (nurse), pre-existing primary headache diagnosis, headache intensity and depression on the frequency of PPE-associated headaches. Depression indirectly mediated the effects of headache intensity and sleep quality on headache frequency. (All P < 0.05).This study provided a path analysis model that illustrates the relationships between PPE-associated headaches frequency and its related factors among healthcare workers during the COVID-19 pandemic. It is crucial to the management of PPE-associated headaches to reduce its consequences for frontline healthcare workers.© 2024 The Authors. Published by Elsevier Ltd.