BACKGROUND: Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease linked to skin microbiome dysbiosis with reduced bacterial diversity and elevated relative abundance of Staphylococcus aureus (S. aureus). OBJECTIVES: We aimed to characterize the yet-incompletely understood association between the skin microbiome and patients' demographic and clinical cofactors in relation to AD severity. METHODS: The skin microbiome in 48 adult moderate-to-severe AD patients was investigated using next-generation deep sequencing (16S rRNA gene, V1-V3 region) followed by denoising (DADA2) to obtain amplicon sequence variant (ASV) composition. RESULTS: In lesional skin, AD severity was associated with S. aureus relative abundance (rS =0.53, p<0.001) and slightly better with the microbiome diversity measure Evenness (rS =-0.58, p<0.001), but not with Richness. Multiple regression confirmed the association of AD severity with microbiome diversity, including Shannon (in lesional skin, p<0.001), Evenness (in non-lesional skin, p=0.015), or S. aureus relative abundance (p<0.012), and with patient's IgE levels (p<0.001), race (p<0.032), age (p<0.034) and sex (p=0.012). The lesional model explained 62% of the variation in AD severity, and the non-lesional model 50% of the variation. CONCLUSIONS: Our results specify the frequently reported "reduced diversity" of the AD-related skin microbiome to reduced Evenness, which was in turn mainly driven by S. aureus relative abundance, rather than to a reduced microbiome Richness. Finding associations between AD severity, the skin microbiome and patient's cofactors is a key aspect in developing new personalized AD treatments, particularly those targeting the AD microbiome.