Background <p>The brain is man’s second-fattiest organ and shows a remarkable lipid diversity. Despite recent advances in lipidomics, much remains unknown about the connection between blood lipids and the brain. Therefore, we investigated the relation between circulating lipid levels and cortical thickness and brain volumes.</p> Methods <p>We related blood levels of ~ 1000 lipid species and fatty acid composite measures to cortical thickness, and total brain, white matter and grey matter volume in the Rhineland Study (<i>n</i> = 3,248) using linear regression models, adjusting for sex, age and low-density and high-density lipoprotein cholesterol. To assess region-specific effects in the relation between lipids and cortical thickness, we performed a cortex-wide vertex-based analysis on our top hits.</p> Results <p>Chain length and degree of saturation influenced a lipid’s effect across different markers of brain health (cortical thickness, brain volumes). Specifically, odd-chained and 18-carbon carrying lipids were mostly associated with a thicker cortex and larger total, grey and white matter volume, whereas 16-carbon carrying and highly unsaturated (&gt; 4 bonds) lipids were associated with a thinner cortex and smaller brain volumes. Furthermore, we found that lipids were mainly associated with regions outside of the pre-frontal cortex and related to the two hemispheres asymmetrically.</p> Conclusions <p>Investigation of within-class relative lipid concentrations suggested that higher levels of odd-chained and 18-carbon carrying lipids and lower levels of polyunsaturated and 16-carbon carrying lipids could be crucial for brain structure. Our research highlights potential targets to improve brain health and underscores that lipid profiles, rather than total lipid concentrations, are critical.</p>