BACKGROUND: Over-the-counter analgesic (OTCA) use is increasingly common and may have potential harmful side effects. The primary reason for using analgesics is headache symptoms. Whether OTCA use for headache is sensitive to psychosocial and social circumstances is an understudied topic. OBJECTIVES: The purpose of this study was to examine the combined effect of socioeconomic position (SEP) and perceived stress on OTCA use for headache. An additional objective was to determine whether sense of coherence (SOC) modifies the association. METHODS: Data derived from the cross-sectional "Danish Lifestyle and Medicine Use Study," 2009. The study population consisted of men and women ages 25-44 years (n = 955). The dependent variable was OTCA use for headache within the past 14 days. The independent variables were SEP, perceived stress, and SOC. Gender, headache prevalence, and response method were included as covariates. Associations were examined by means of logistic regression analyses, and reported as odds ratios (ORs) with 95% confidence intervals. RESULTS: The OR for OTCA use was 1.42 (0.94-2.14) (statistically nonsignificant) among participants with low SEP but no perceived stress (reference high SEP, no perceived stress), 2.09 (1.53-2.85) for participants with perceived stress and high SEP, and 2.65 (1.66-4.25) among participants with perceived stress and low SEP. In analysis, stratified by SOC associations were stronger among participants with low SOC than among those with high SOC. CONCLUSIONS: Individuals exposed to both low SEP and high perceived stress have high odds for using OTCA for headache, apparently higher than participants only exposed to 1 of these factors. SOC may act as a buffer against the harmful effects of perceived stress and low SEP on OTCA use. Health care professionals and policymakers need to be aware of the sensitivity of OTCA use to psychosocial and social circumstances.