Several risk factors leading to loosening of the glenoid have been described; however, there is no detailed information available on the exact numbers or percentages for each patient-related risk factor, implant-related risk factor, or risk factors related to surgical technique. Therefore, the aim of this multicenter study was to analyze these risk factors in a large cohort of patients treated with a 3rd-generation cemented total shoulder arthroplasty. Four-hundred seventy-one shoulder arthroplasties with a mean follow-up of 8.1 years were included. There were 318 women and 153 men. The mean age at the time of arthroplasty was 68 (range 35–90) years. The dominant shoulder was treated in 294 cases and the nondominant in 177. The following risk factors for loosening of the cemented keeled glenoid component were examined: gender, age, hand dominance, glenoid morphology, reaming on the glenoid side (reaming down the complete subchondral bone layer), glenohumeral mismatch, glenoid component design, and fatty degeneration of the rotator cuff. No influence on radiographic glenoid loosening was found for patient age at surgery, gender, hand dominance, preparation technique on the glenoid side, or fatty degeneration of the rotator cuff (p > 0.067). Excessive reaming on the native glenoid led to a 3.7-fold higher risk for glenoid component loosening (p < 0.001). A glenohumeral mismatch <6 mm was associated with higher radiographic loosening rates (p < 0.03). The use of a flat-back glenoid component led to a 3.1-fold higher risk for radiographic loosening compared to convex-back glenoids (p < 0.001). B2 glenoids had a higher risk for radiographic loosening compared to A1 (2.3-fold), A2 (3.6-fold), and B1 (2.7-fold) glenoids (p < 0.001). Based on a large and homogenous cohort of patients, this study has shown several risk factors for loosening of a cemented glenoid component in the midterm and long term. The loosening rates of cemented keeled glenoid components in primary osteoarthritis could possibly be reduced by optimizing surgical technique, implant configuration, and patient selection. Further long-term studies are necessary to confirm these findings.