Abstract Introduction The importance of sex as a biological variable on the relationship of migraine and sleep disturbance has not been well-characterized. Given evidence of 1)bidirectional relationships of poor sleep and migraine severity and 2)greater activation of brain regions involved in emotional processing in women compared to men with migraine, we hypothesized that sleep architectural disruption may contribute to sex-specific differences in quality of life measures, particularly those attributed to emotional processing. Methods This was a retrospective cohort study of migraine patients aged >18 years seen in the Cleveland Clinic headache program with polysomnogram data. Migraine burden was measured by the 20-item migraine-specific quality of life(MSQOL) encompassing three domains: emotional function(EF), role function-preventative, and role function-restrictive. Linear regression models were used to assess the association of each MSQOL domain with sleep architectural measures and the statistical interaction with sex was examined. Coefficients and 95% confidence intervals were estimated and compared with adjustment of age, race, body mass index(BMI) and comorbidities. Results Of 245 patients with migraine,37(15.1%) were male. Males had higher AHI (10.0 [5.3, 18.5] vs. 5.7[1.8, 11.4], p=0.006). The difference in MSQOL-EF scores was not statistically significant (males:73.3[53.3,86.7] vs. females:60.0 [33.3,80.0], p= 0.066). There was no statistical difference in percent N2 or REM between sexes, though males had greater %N1, and lower %N3 (10.9[5.9,19.2] vs. 6.6[4.1,11.9],p=0.039). The association of MSQOL-EF with percent of N2 and REM sleep differed by sex. For each 5% increase in N2, there was a 5% reduction of MSQOL-EF 2.08 (-2.08, 95%CI [-6.86,2.70],p=0.39) in females compared to a 6.84 reduction in males (-6.84, 95%CI [-15.9,2.22],p=0.14), p-value for interaction=0.044. For each 5% increase in REM, MSQOL-EF increased 1.26 (1.26, 95%CI [-3.68,6.21],p=0.61) in females, and increased by 6.27 in males (6.27, 95%CI [-3.11,15.6], p=0.19),p-value for interaction=0.044. Conclusion Although males had greater sleep disruption compared to females, there was no significant difference in MSQOL-EF scores. However, sex-specific differences of extent of sleep stage composition and MSQOL-EF were observed suggesting influence of sleep architectural alterations on greater responsivity of migraine emotional processing in men versus women. Future investigation should better characterize longitudinal relationships and underlying neurobiological mechanisms underlying these findings. Support (if any) Association of Migraine Disorders