Abstract Background Although chronic hand eczema (CHE) is a highly prevalent and disabling skin disease, it is currently unknown if CHE is associated with systemic inflammation. Objective To characterize the plasma inflammatory signature of CHE. Methods Using Proximity Extension Assay technology, we assessed 266 inflammatory and cardiovascular disease risk proteins in the plasma of 40 healthy controls, 57 patients with atopic dermatitis (AD) with active lesions, 11 with CHE and a history of AD (CHEPREVIOUS_AD), and 40 with CHE and no history of AD (CHENO_AD). Filaggrin gene mutation status was also assessed. Protein expression was compared between groups and according to disease severity. Correlation analyses for biomarkers, clinical- and self-reported variables were performed. Results Very severe CHENO_AD was associated with systemic inflammation when compared with controls. Levels of T helper cell (Th)2, Th1, general inflammation and eosinophil activation markers increased with severity of CHENO_AD, primarily being significantly increased in very severe disease. Significant, positive correlations were found between markers from these pathways and severity of CHENO_AD. Moderate-to-severe, but not mild AD, displayed systemic inflammation. Th2 markers chemokine (C-C motif) ligand (CCL)17 and CCL13 were the top differentially expressed proteins in both very severe CHENO_AD and moderate-to-severe AD, showing a higher fold change and significance in AD. CCL17 and CCL13 levels further correlated positively with disease severity in both CHENO_AD and AD. Conclusion Systemic Th2-driven inflammation is shared between very severe, CHE without AD and moderate-to-severe AD, suggesting that Th2 cell targeting could be effective in several CHE subtypes.