To investigate the impact of the Charlson and Elixhauser comorbidity indices on patient-reported outcomes measures (PROMs) following shoulder arthroplasty. Patients undergoing total shoulder arthroplasty (TSA), reverse shoulder arthroplasty (RSA), or hemiarthroplasty (HA) from 2016 to 2018 were identified, along with the Charlson and Elixhauser comorbidities listed as their secondary diagnoses in the electronic medical records. Patients were matched to our institution's registry to obtain their PROMs, including shoulder-specific (American Shoulder and Elbow Society (ASES) and Shoulder Activity Scale (SAS)) and general health scales (12-Item Short Form Survey (SF-12) and Patient-Reported Outcomes Measurement Information System-Pain Interference). Linear regression models adjusting for age and sex were used to evaluate the association between increasing number of comorbidities and PROM scores. A total of 1,817 shoulder arthroplasties were performed: 1,017 (56%) TSA, 726 (40%) RSA, and 74 (4%) HA. The mean age was 67 years (SD 10), and 936 (52%) of the patients were female. The most common comorbidities were obesity (1,256, 69%) and hypertension (990, 55%). Patients with more comorbidities had lower ASES and SAS scores at baseline (p < 0.001). Elixhauser comorbidities continued to negatively impact ASES and SAS scores at one year (p = 0.002) and two-year follow-up (p = 0.002). Patients with more comorbidities reported greater pain interference on PROMIS at baseline (p = 0.007), but not at two years. Higher number of Charlson comorbidities were associated with lower scores on the SF-12 mental component at baseline (p < 0.001) and two years (p = 0.020). Higher number of Elixhauser comorbidities were associated with lower SF-12 physical component scores at baseline (p < 0.001) and two years (p = 0.004). Higher number of comorbidities was associated with lower baseline scores and worse outcomes on both shoulder-specific and general health PROMs. The presence of specific comorbidities may be used during shared decision-making to manage expectations for patients undergoing shoulder arthroplasty. Cite this article: Bone Joint J2021;103-B(5):964-970.