BACKGROUND. Therapies can reduce the risk of heart failure (HF) development and progression in type 2 diabetes (T2D); nevertheless, the risk of these outcomes is greater in females than in males. METHODS. To investigate sex-differences in HF development and progression, we compared baseline circulating proteins (Olink® Cardiovascular II panel) in males and females with T2D and recent acute coronary syndrome (ACS) for the outcome of heart failure hospitalization (HFH). Data were from the placebo-controlled Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. Pathophysiological sex-differences were interpreted with network and pathway overrepresentation analyses. RESULTS. The EXAMINE trial enrolled 5,380 participants (32.1% females) with biomarker data available in 95.4% of individuals. Analyses revealed 43 biomarkers were differentially expressed in HFH, of which 18 were sex-specific. Among these 43 biomarkers, interleukin-6 was identified as a central node for the pathogenesis of HFH in both females and in males. Additional pathway overrepresentation analyses demonstrated that biomarkers associated with inflammatory pathways related to endothelial-dysfunction and cardiac fibrosis were more up-regulated in females than males with HFH. Differential expression of 3 biomarkers (pentraxin-related protein 3, hydroxyacid oxidase 1, and carbonic anhydrase 5A) was independently associated with an increased risk of HFH in females but not in males (interaction p<0.05). CONCLUSION. In males and females with T2DM and ACS, interleukin-6 appears to be central in the pathogenesis of HF. Females exhibit higher levels of circulating proteins related to immunological pathways, reflecting sex-specific differences underlying HF development and progression.