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Obesity-associated inflammation predisposes to cardiovascular disease (CVD). We investigated the association of biological sex with the plasma inflammatory protein profile in individuals with obesity. Clinical and proteomic data from 450 women and men with a body mass index (BMI) > 27 kg/m² without known CVD participating in the FAT associated CardiOvasculaR dysfunction study were analysed. The Olink Target 96 inflammation panel was employed in biobank samples. Hypertension was more prevalent among men, while age, BMI, and prevalences of obesity, diabetes and smoking did not differ between the sexes (all p > 0.05). In multivariable analyses, obesity was associated with downregulation of interleukin (IL) 7, IL 12 subunit beta, IL 6, and C-X-C motif chemokine 11, and upregulation of sulfotransferase 1A1 and SIR2-like protein 2 in women (all p < 0.05). In men, obesity was associated with downregulation of monocyte chemotactic protein 3, tumour necrosis factor superfamily member 12, IL 10 and protein S100-A12, and upregulation of neurotrophin-3 (all p < 0.05). In sum, the targeted protein profile in obesity differed by biological sex and there was no overlap in the differentially regulated proteins between women and men with obesity. The results suggest that pathophysiological mechanisms in obesity-associated inflammation and immune dysregulation may be sex-biased.