Background: Headache is the most frequent neurological adverse event following SARS-CoV-2 vaccines. We investigated the frequency, characteristics, and factors associated with post-vaccination headaches, including their occurrence and prolongation (≥ 48 h)., Methods: In this observational cross-sectional cohort study, retrospective data collected between April 2021-March 2022 were analyzed. Univariate and multivariate logistic regressions were used to evaluate the effect of clinicodemographic factors on the odds of post-vaccination headache occurrence and prolongation., Results: Of 2,500 people who were randomly sent the questionnaire, 1822 (mean age: 34.49 ± 11.09, female: 71.5%) were included. Headache prevalence following the first (V 1 ), second (V 2 ), and third (V 3 ) dose was 36.5, 23.3, and 21.7%, respectively ( p < 0.001). Post-vaccination headaches were mainly tension-type (46.5%), followed by migraine-like (36.1%). Headaches were mainly bilateral (69.7%), pressing (54.3%), moderate (51.0%), and analgesic-responsive (63.0%). They mainly initiated 10 h [4.0, 24.0] after vaccination and lasted 24 h [4.0, 48.0]. After adjusting for age and sex, primary headaches (V 1 : aOR: 1.32 [95%CI: 1.08, 1.62], V 2 : 1.64 [1.15, 2.35]), post-COVID-19 headaches (V 2 : 2.02 [1.26, 3.31], V 3 : 2.83 [1.17, 7.47]), headaches following the previous dose (V 1 for V 2 : 30.52 [19.29, 50.15], V 1 for V 3 : 3.78 [1.80, 7.96], V 2 for V 3 : 12.41 [4.73, 35.88]), vector vaccines (V 1 : 3.88 [3.07, 4.92], V 2 : 2.44 [1.70, 3.52], V 3 : 4.34 [1.78, 12.29]), and post-vaccination fever (V 1 : 4.72 [3.79, 5.90], V 2 : 6.85 [4.68, 10.10], V 3 : 9.74 [4.56, 22.10]) increased the odds of post-vaccination headaches. Furthermore, while primary headaches (V 1 : 0.63 [0.44, 0.90]) and post-COVID-19 headaches (V 1 : 0.01 [0.00, 0.05]) reduced the odds of prolonged post-vaccination headaches, psychiatric disorders (V 1 : 2.58 [1.05, 6.45]), headaches lasting ≥48 h following the previous dose (V 1 for V 2 : 3.10 [1.08, 10.31]), and migraine-like headaches at the same dose (V 3 : 5.39 [1.15, 32.47]) increased this odds., Conclusion: Patients with primary headaches, post-COVID-19 headaches, or headaches following the previous dose, as well as vector-vaccine receivers and those with post-vaccination fever, were at increased risk of post-SARS-CoV-2-vaccination headaches. Primary headaches and post-COVID-19 headaches reduced the odds of prolonged post-vaccination headaches. However, longer-lasting headaches following the previous dose, migraine-like headaches at the same dose, and psychiatric disorders increased this odd., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jameie, Togha, Azizmohammad Looha, Jafari, Yazdan Panah, Hemmati and Nasergivehchi.)