BackgroundA recent randomized controlled trial (RCT) investigating the effect of chiropractic manipulation in 199 children aged 7–14 years with recurrent headaches demonstrated a significant reduction of number of days with headache and a better global perceived effect (GPE) in the chiropractic manipulation group compared to a sham manipulation group. However, potential modifiers for the effectiveness of chiropractic manipulation of children with recurrent headaches have never been identified. The present study is a secondary analysis of data from that RCT and will investigate potential effect modifiers for the benefit of chiropractic manipulation for children with headache.MethodsSixteen potential effect modifiers were identified from the literature and a summary index was prespecified based on clinical experience. Relevant variables were extracted from baseline questionnaires, and outcomes were obtained by means of short text messages. The modifying effect of the candidate variables was assessed by fitting interaction models to the data of the RCT. In addition, an attempt to define a new summary index was made.ResultsThe prespecified index showed no modifying effect. Four single variables demonstrated a treatment effect difference of more than 1 day with headache per week between the lower and the upper end of the spectrum: intensity of headache(p= 0.122),Frequency of headache(p= 0.031),sleep duration(p= 0.243), andSocioeconomic status(p= 0.082). Five variables had a treatment effect difference of more than 0.7 points on the GPE scale between the lower and the upper end of the spectrum: Frequency of headache (p= 0.056),Sport activity(p= 0.110),Sleep duration(p= 0.080),History of neck pain(p= 0.011), andHeadache in the family(0.050). A new summary index could be constructed giving highest weight toHistory of neck painandHeadache in the familyandFrequency of headache. The index suggests a difference of about 1 point in GPE between low and high values of the index.ConclusionChiropractic manipulation offers a moderate benefit for a broad spectrum of children. However, it cannot be excluded that specific headache characteristics, family factors, or a history of neck pain may modify the effect. This question must be addressed in future studies.Trial registration: ClinicalTrials.gov (Albers et al in Curr Pain Headache Rep 19:3–4, 2015), identifier NCT02684916, registered 02/18/2016—retrospectively registered.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12998-023-00492-2.