Background: Health-related quality of life (HRQOL) is impaired in chronic obstructive pulmonary disease (COPD) patients, but determining factors for HRQOL are still not unequivocal. This study measures HRQOL among patients with COPD and aims to determine factors associated with HRQOL. Methods: Data for cross-sectional analyses were obtained from the baseline of a cohort study. The study population includes adult COPD patients (disease duration >= 3 months), recruited from primary and secondary care settings in Germany, without acute psychiatric/neurologic disease (exception: affective/anxiety disorders). HRQOL was assessed using the Short-Form 12 (SF-12) Health Survey Questionnaire, comprising a physical and mental component. Independent variables encompass socio-demographic, disease-specific, treatment-related and psychological factors. Multivariable linear regression analyses were conducted. Results: In total, 206 COPD patients (60.7% male; mean age: 65.3 years) took part in the study. In multivariable analysis, the physical component score showed a significant negative association with the COPD Assessment Test (CAT) (P<0.001) and a higher total number of prescribed medications (P=0.001). A higher forced expiratory volume in 1 second (FEV1) value in percent predicted was significantly related to the physical component score in a positive manner (P=0.006). The mental component score was significantly associated with elevated patient-reported symptoms of anxiety (P=0.002) or depression (P<0.001), measured by the hospital anxiety and depression scale (HADS) in a negative way. Like for the physical component score (P<0.001), a worse CAT score was significantly associated with a lower mental component score (P=0.033). Conclusions: Focusing on patient reported outcomes and screening for depression and anxiety with potential successive treatment might be promising approaches to improve HRQOL in patients with COPD.