Abstract Purpose Health-related quality of life (HRQoL) becomes increasingly relevant in an aging society. Functional outcome (FO) and the patient-reported outcome (PRO) after surgical treatment of proximal humerus fractures (PHF) depends on numerous factors, including patient- and injury-specific factors. There is little evidence on how the FO and the PRO vary in different settings such as monotrauma or multiple injuries, even though the PHF is one of the more frequent fractures. In addition, to a previous study, on multiple injured patients and upper extremity injuries, the aim of the current study was to investigate the impact of multiple injuries, quantified by the ISS, on the FO and PRO after surgically treated PHF by PHILOS. Methods A retrospective cohort-study was conducted with an additional follow-up by a questionnaire. HRQoL tools such as range of motion (ROM), the Quick-Disability of Arm Shoulder and Hand score (DASH), EuroQol Five Dimension Three Levels (EQ-5D-3L), and EuroQol VAS (EQ-VAS) were used. The study-population was stratified according to ISS obtained based on information at discharge into Group I/M-H (ISS < 16 points) and Group PT–H (ISS ≥ 16). Median outcome scores were calculated and presented. Inclusion criteria: adult patients (> 18 years) with PHF treated at one academic Level 1 trauma center between 2007 and 2017 with Proximal Humeral Inter-Locking System (PHILOS) and preoperative CT-scan. Group stratification according Injury Severity Score (ISS): Group PT–H (ISS ≥ 16 points) and Group I/M-H (ISS < 16 points). Exclusion criteria: oncology patients, genetic disorders affecting the musculoskeletal system, paralysis or inability to move upper extremity prior or after injury, additional ipsilateral upper limb fractures, open injuries, associated vascular injuries as well brachial plexus injuries and nerve damages. Follow-up 5–10 years including PRO: EQ-5D-3L and EQ-VAS. FO, including DASH and ROM. The ROM was measured 1 year after PHILOS. Results Inclusion of 75 patients, mean age at injury was 49.9 (± 17.6) years. The average follow-up period in Group I/M-H was 6.18 years (± 3.5), and in Group PT–H 5.58 years (± 3.1). The ISS in the Group I/M-H was 6.89 (± 2.5) points, compared to 21.7 (± 5.3) points in Group PT–H (p ≤ 0.001). The DASH-score in Group I/M-H was 9.86 (± 13.12 and in Group PT–H 12.43 (± 15.51, n.s.). The EQ-VAS in Group I/M-H was 78.13 (± 19.77) points compared with 74.13 (± 19.43, n.s.) in Group PT–H. DASH, EQ-VAS as well as ROM were comparable in Groups I/M-H and PT–H (9.9 ± 13.1 versus 12.4 ± 15.5, n.s.). The EQ-5D-3L in Group I/M-H was 0.86 (± 0.23) points compared to Group PT–H 0.72 (± 0.26, p ≤ 0.017). No significant differences could be found in Group I/M-H and PT–H in the severity of traumatic brain injury (TBI). A multivariable regression analyses was performed for DASH, EQ-5D-3L and EQ-VAS. All three outcome metrics were correlated. There was a significant difference between the EQ-5D-3L and the ISS (Beta-Coefficient was 0.86, 95% low was 0.75, 95% high was 0.99, p ≤ 0.041). No significant correlation could be found comparing DASH, EQ-5D-3L and EQ-VAS to age, gender and TBIs. Conclusion Multiple injuries did not affect the DASH, ROM or EQ-VAS after PHILOS; but a higher ISS negatively affected the EQ-5D-EL. While the ROM and DASH aim to be objective measurements of functionality, EQ-5D-3L and EQ-VAS represent the patients’ PRO. The FO and PRO outcomes are not substitutable, and both should be taken into consideration during follow-up visits of multiple injured patients. Future research should prospectively explore whether the findings of this study can be recreated using a larger study population and investigate if different FO and PRO parameters come to similar conclusions. The gained information could be used for an enhanced long-term evaluation of patients who suffered a PHF from multiple injuries to meet their multifarious conditions. Level of evidence II.