BackgroundExposure to different concentration levels of fatty acids (FAs) may have an impact on depression. However, previous studies using individual FAs may not reflect the performance of mixtures of various FAs, and the associations of FA patterns with depression remain unclear.MethodsWe conducted the cross-sectional analysis in 792 adults aged 18 and older with available serum FAs and depression screening data in the National Health and Nutrition Examination Survey (NHANES) 2011–2012. The serum concentrations of thirty FAs were measured using gas chromatography-mass spectrometry and their percentage compositions were subsequently calculated. Depression was defined as the Patient Health Questionnaire-9 score ≥ 10. We employed principal component analysis to derive serum FA patterns. We examined the association between these patterns and depression in the overall population and various subgroups through survey-weighted logistic regression.ResultsFour distinct patterns of serum FAs were identified: ‘high eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); low docosatetraenoic acid (DTA) and docosapentaenoic acid (DPA) n-6’, ‘high long-chain saturated FA and long chain FA’, ‘low median-chain saturated FA and myristoleic acid’ and ‘low capric acid and lauric acid; high gamma-linolenic acid (GLA) and stearidonic acid (SDA)’ pattern. Individuals in the high tertile of ‘high EPA and DHA; low DTA and DPA n-6’ pattern score had 0.46 (95% CI: 0.22, 0.93) lower odds of developing depression compared to individuals in the lowest tertile after adjusting for confounders such as age, sex, physical activity and total energy intake, etc. The odds ratio (OR) of depression was increased in the population with the highest tertile of ‘low capric acid and lauric acid; high GLA and SDA’ pattern (OR: 2.45, 95% CI: 1.24, 4.83). In subgroup analyses, we observed that the association between ‘high EPA and DHA; low DTA and DPA n-6’ and depression persisted among specific demographic and lifestyle subgroups, including females, non-Mexican Americans, non-obese, those aged over 60 years, smokers and drinkers. Similarly, ‘low capric acid and lauric acid; high GLA and SDA’ showed stable associations in female, non-Mexican Americans and smokers.ConclusionsSerum FA patterns are associated with depression, and their relationships vary across sex, race, BMI, age, smoking and drinking subgroups, highlighting the importance of considering specific FA patterns within these demographic and lifestyle categories. Utilization of combined FA administration may serve as a mitigation measure against depression in these specific populations.