Background: Fatty infiltration (FI) is a key prognostic factor that affects outcomes after rotator cuff repair and is radiologically evaluated using the Goutallier classification. The purpose of this study was to assess alterations in gene and protein expression according to the Goutallier classification in the supraspinatus muscle and any relationships among various gene expression profiles. Methods: Twenty-four samples of the supraspinatus muscle from 12 patients with a high FI grade (grade 3 or 4) and 12 patients with a low FI grade (grade 1 or 2) with medium-sized tears were acquired during arthroscopic surgery. Alterations in the expression of genes and proteins associated with adipogenesis, fibrosis, inflammation, and muscle atrophy were compared between the highand low-FI groups using reverse-transcription quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Results: mRNA expression of not only the adipogenic genes (peroxisome proliferator-activated receptor y and CCAAT/enhancer-binding protein cc; P < .001 and P = .020) but also the fibrosis-related gene (cc-smooth muscle actin; P < .001), inflammation-related genes (interleukin [IL]-10 and tumor necrosis factor cc; P = .041 and P = .039), and muscle atrophy-related genes (atrogin 1 and myostatin; P = .006 and P < .001) was higher in the high-FI group compared with that in the low-FI group. In addition, adipogenic gene expression was significantly correlated with the expression of other categories of genes (all P < .05, except atrogin 1). A correlation of gene and protein expression was observed for IL-10 (P = .027) and myostatin (P = .029). Conclusions: The radiologic grading of FI was associated with the expression of various genes, including adipogenic, fibrotic, inflammatory, and atrophy-related genes, and these genes were closely correlated with each other in terms of expression. This information could be helpful in patient counseling. (c) 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.