Fatty acid (FA) metabolism has been involved in acne vulgaris, a common inflammatory skin disease frequently observed in adolescents and adults, but it remains poorly defined whether the distributions or location of FA in facial sebum and those in the circulation differentially correlate with the disease. In a cohort of 47 moderate acne patients and 40 controls, sebum samples from forehead and chin areas were collected using Sebutape adhesive patches, and erythrocytes were separated from the fasting blood. Total FAs were analyzed by the gas chromatograph-mass spectrometry method. Compared to control female subjects, female patients showed increased levels of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) from both facial areas, whereas decreased levels of polyunsaturated fatty acids (PUFAs) from chin areas were observed. Interestingly, the levels of docosahexaenoic acid (DHA) in the circulating erythrocytes were significantly decreased in male patients compared with control. In addition, DHA levels in erythrocytes were positively correlated with PUFAs from sebum only in male subjects. Furthermore, female patients with moderate acne had more severe sebum abnormity and chin-specific FA profiles, consistent with higher acne incidences than males in adulthood, especially in the chin areas. Importantly, serum insulin-like growth factor 1 (IGF-1) levels were positively correlated with SFAs and MUFAs from sebum only in male subjects. In summary, differential spatial FA distributions in facial sebum and correlation with those in erythrocytes and IGF1 levels in serum may shed some light on the pathology of acne in male and female adults.