Background: Breast cancer is a heterogeneous disease with a wide range of outcomes. Among the intrinsic breast cancer subtypes, luminal A tumors are considered to have a favorable prognosis. However, molecular studies characterizing the genomic landscape of luminal A tumors revealed a molecular heterogeneity within this subtype, which also translated to variability in survival. A better understanding of the biology of this tumor subgroup is therefore needed to determine the appropriate therapeutic strategy. The aims of the study were to determine the frequency of high-risk luminal A tumors in a real life cohort of early breast cancers and provide a proteomic characterization of this subgroup using a mass spectrometry approach. Methods: 222 early breast cancer patients with hormone receptor positive and HER2 negative tumors treated at our institution had a PAM50-based genomic assay Prosigna to estimate their risk of recurrence. This assay assigned each tumor sample to an intrinsic molecular subtype of breast cancer. Luminal A and B tumors were analyzed with MALDI mass spectrometry imaging combined with microproteomics, a spatially-resolved on-tissue shotgun proteomic technology, to determine the proteomic profiles of both cancer cells and stroma. Results: Among the 129 luminal A breast cancers identified in our cohort, 67 (51%) had a risk of distant recurrence of 10% or more (32% had a 10% to 15% risk, and 19% a risk greater than 15%). High-risk luminal A tumors had a distinctive proteomic profile compared to low-risk luminal A or to luminal B tumors. Overexpression of the methionine biosynthesis pathway was the main differential protein expression observed in cancer cells and stroma of high-risk luminal A. Inflammation mediated by chemokine and cytokine signaling pathway and integrin signaling were also overexpressed in high risk luminal A compared to luminal B. In the stroma of luminal B tumors, EGR signaling, Ras and FGF pathways and angiogenesis were overexpressed compared to high-risk luminal A tumors. Conclusions: Real life data showed a significant proportion of high-risk luminal A breast cancers. MALDI mass spectrometry proteomics revealed distinctive tumor and microenvironment profiles in this breast cancer subgroup.