Background: Although the cause of rotator cuff tearing is likely multifactorial and a genetic predisposition has been proposed, the biochemical basis remains unknown. Purpose: To determine gene expression profiles in torn rotator cuff tendon tissue through use of RNA sequencing. Study Design: Controlled laboratory study. Methods: The supraspinatus tendon edge was biopsied in 24 patients undergoing arthroscopic rotator cuff repair for full-thickness supraspinatus rotator cuff tears. The supraspinatus tendon was also biopsied in 9 patients undergoing open reduction and internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and sequenced. Differential gene expression was analyzed between the tear and control groups, and a secondary analysis was conducted between groups defined by an unbiased clustering. Results: Tear and control transcriptomes demonstrated significant differential expression in more than 3000 genes. The identified differential genes were highlighted in pathways involved in inflammation in control patients and extracellular matrix generation in patients with tears. Secondary analysis using unsupervised and thus unbiased hierarchical clustering revealed 2 clusters (c2 and c3). Cluster c3 contained smaller ( P < .001) and less retracted ( P = .018) tears (ie, tears earlier in the progression of rotator cuff disease) with increased expression of hypoxia target genes. Cluster c2 contained larger, more retracted tears (ie, tears further in the progression of rotator cuff disease) with increased expression of endothelial cell markers and chronic inflammation target genes. Tears in c2 had significantly worse healing rates compared with tears in c3 (0% vs 89%; P = .007). Conclusion: Smaller, less retracted tears had increased expression of hypoxia target genes and improved healing, whereas larger, more retracted tears were associated with endothelial cell markers and worse healing. Thus, hypoxia may be the inciting event for tear development, whereas with tear enlargement, a chronic, inflammatory, angiogenic process may predominate. Clinical Relevance: Identification of differential gene expression in rotator cuff tears may be a reliable tool to predict repair healing in the future.