Several studies have shown that major depression is accompanied by alterations in serum fatty acid composition, e.g. reduced n-3 fatty acids and an increased 20:4n-6/20:5n-3 ratio in serum. Moreover, pregnancy leads to depletion of maternal serum 22:6n-3 and after delivery maternal serum 22:6n-3 steadily declines further. Therefore, the aim of the present study was to investigate whether the postpartum fatty acid profile of maternal serum phospholipids (PL) and cholesteryl esters (CE) differs in women who develop postpartum depression compared to controls. We compared the fatty acid composition shortly after delivery of 10 women who developed postpartum depression and 38 women who did not. After delivery, 22:6n-3 and the sum of the n-3 fatty acids in PL and CE was significantly lower in the group of mothers who developed a postpartum depression. The ratio of Sigman-6/Sigman-3 fatty acids in PL was, postpartum, significantly higher in the depressed group as compared to the controls. The abnormalities in fatty acid status previously observed in major depression are now also confirmed in postpartum depression. These results indicate that pregnant women who are at risk to develop postpartum depression may benefit from a prophylactic treatment with n-3 PUFAs, such as a combination of 20:5n-3 and 22:6n-3.