Aims Experimental and epidemiological studies reported controversial data on the role of omentin in type 2 diabetes and cardiovascular diseases. This study aimed to characterise the impact of omentin on the secretome of human adipocytes to analyse the enrichment of these proteins in metabolic and cellular signalling pathways underlying its physiological function. Material/methods Differentiated primary human adipocytes were treated without or with 500 or 2000 ng/mL omentin for 24 hours. The secretome was analysed by liquid chromatography coupled tandem-mass spectrometry. Differences in protein secretion between untreated and omentin-treated adipocytes were compared using a paired t-test. Other potential upstream regulators and the overrepresentation in canonical pathways of omentin-stimulated proteins were analysed using Ingenuity Pathway Analysis. Results The supernatant of adipocytes contained 3493 proteins, of which 140 were differentially secreted by both concentrations of omentin compared with untreated adipocytes. Among the most strongly increased proteins, tumour necrosis factor-inducible gene 6 protein (TNFAIP6) was increased by 140-fold in the supernatant. Omentin-regulated proteins were overrepresented in seven canonical pathways including eukaryotic initiation factor 2 signalling, complement system, and inhibition of matrix metalloproteases. We further identified 25 other potential upstream activators of omentin-regulated proteins, mainly pro-inflammatory cytokines and transcription regulators including NF kappa B. Conclusions In differentiated human adipocytes, the release of the anti-inflammatory TNFAIP6 might be part of a counterregulatory response to the pro-inflammatory action of omentin. Omentin-regulated proteins were overrepresented in pathways indicating cellular stress, a pro-inflammatory environment and a crosstalk with other organs. Other potential activators of omentin-regulated proteins point towards a central role of NF kappa B activation in the omentin-induced secretory process.