HYPOTHESIS AND BACKGROUND: In complex proximal humerus fractures, bone resorption of the greater tuberosity is sometimes observed after open reduction and internal fixation (ORIF). However, this has not been well characterized and risk factors for resorption are not completely understood. We aimed (1) to identify the risk factors associated with bone resorption of the greater tuberosity; and (2) to quantify the geometric and bone density characteristics associated with bone resorption using 3-dimensional computed tomography (CT) models, in complex proximal humerus fractures treated with ORIF. METHODS: We identified a retrospective cohort of 136 patients who underwent ORIF of 3-part or 4-part proximal humerus fractures and 30 patients developed greater tuberosity resorption after ORIF. We collected demographics and fracture- and surgery-related characteristics, and performed multivariable logistic regression analysis to identify factors independently associated with the development of greater tuberosity resorption. Furthermore, we identified 30 age- and sex-matched patients using propensity score matching to perform quantitative fragment specific analysis using 3-dimensional CT models. After the fragment of the greater tuberosity was identified, the number of fragments, the relative fragment volume to the humeral head and the relative bone density to the coracoid process were calculated. Measurements were compared between matched case-control groups. RESULTS: We found that an unreduced greater tuberosity (odds ratio = 10.9; p < 0.001), inadequate medial support at the calcar (odds ratio = 15.0; p < 0.001) and the use of an intramedullary fibular strut (odds ratio = 4.5; p = 0.018) were independently associated with a higher risk for bone resorption. Quantitative fragment specific analysis showed that greater tuberosity with a larger number of fragments (5 ± 2 vs. 3 ± 2; p = 0.021), smaller fragments (9.9 ± 3.8% vs. 18.6 ± 4.7%; p < 0.001) and fragments with a lower bone density (66.4 ± 14.3% vs. 88.0 ± 18.4%; p = 0.001) had a higher rate of resorption. DISCUSSION AND CONCLUSION: An unreduced greater tuberosity or inadequate medial support increases the risk of greater tuberosity resorption, as were larger number of fracture fragments, smaller fragments, and lower bone density. Additionally, fibular strut grafting is an independent risk factor for tuberosity resorption. Further study is needed, but alternatives to strut grafting such as femoral head allograft may warrant serious consideration. LEVEL OF EVIDENCE: Level III; Retrospective Case-Control Design; Prognosis Study.