OBJECTIVES: In patients with chronic diseases such as hypercholesterolemia, health-related quality of life (HRQoL) is an important outcome. The objective of the present study was to determine factors associated with an impaired HRQoL after 12 months. METHODS: Patients with hypercholesterolemia were prospectively included in the ORBITAL (Open-label primary care study: Rosuvastatin-Based compliance Initiatives linked To Achievement of LDL goals) Study. Inclusion criteria were hypercholesterolemia with an indication for statin therapy according to the European Guidelines. Follow-up was 12 months. A total of 1961 primary care practices in Germany participated. HRQoL was assessed with the Short Form (SF)-12 health status instrument. RESULTS: Of the 7640 patients included, 47% were high-risk patients in the primary prevention of coronary heart disease, 42% were patients with coronary heart disease, and 11% did not have a priori risk stratification. Physical SF-12 summary scores were inversely associated with risk stratum, however, there was no such association between mental SF-12 summary scores and risk stratum. An impaired physical SF-12 score was associated with increased age, lower educational level, higher body mass index, smoking, existing coronary heart disease, a history of stroke, or a clinical event during follow-up. An impaired mental SF-12 score was associated with younger age, hypertension, or a clinical event during follow-up. CONCLUSIONS: HRQoL in patients with hypercholesterolemia is associated with socioeconomic factors, lifestyle, and clinical events. Effective prevention is thus not only essential for clinical outcome but also for the maintenance of HRQoL in patients with hypercholesterolemia. ClinicalTrials.gov Identifier: NCT00379249.