OBJECTIVE: To examine the association between headache, sense of coherence (SOC), and medicine use for headaches in a community-based sample of adolescents. METHODS: Epidemiological cross-sectional study, encompassing 20 out of 23 schools in the network of health-promoting schools in the county of South Jutland, Denmark. The study population consisted of students from seventh and ninth grade, participation rate 93%, n=1393. The students answered questions on demographic variables, health behavior including medicine use, psychosocial health aspects, and sense of coherence, in an anonymous standardized questionnaire. The outcome measure was self-reported medicine use for headaches. The determinants were headache frequency and SOC measured by Wold and Torsheim's version for children of Antonovsky's 13-item SOC scale. RESULTS: Analyses adjusted for age group, family social class, exposure to bullying, and headache frequency showed increasing odds for medicine use for headaches (hereafter: medicine use) by decreasing SOC. There was no association between SOC and medicine use among students with a rare experience of headaches but a significant and graded association among students with at least weekly experience of headaches, that is, frequency of headaches modified the association between SOC and medicine use. CONCLUSIONS: We found that adolescents with low SOC used medicine to cope with headaches to a greater extent than adolescents with high SOC.