A decreased quality of life was shown for numerous factors at the beginning of the pandemic. However, it is important to identify people who are at-risk for long-term impairments during the pandemic and its aftermath. Within this study, we aimed to investigate quality of life within a German population-based sample (2515 participants; 51.6% female; mean age 50.09 years) during the second year of the pandemic (2021). Our results showed that the majority reported no pandemic-associated change in quality of life at this state of the pandemic. Higher life satisfaction was associated with fewer mental health problems, no pre-existing somatic and psychiatric disorders, higher income, no income loss during the pandemic, living with others, and younger age. In contrast, in a high-risk group encompassing participants with lower quality of life, only mental health, pre-existing somatic disorders, and living alone had significant associations with quality of life, indicating a smaller scope for improvement in this high-risk group. Age, income loss, and depressive symptoms predicted a decrease in quality of life since the beginning of the pandemic. Our results highlight the importance of mental health, especially in times of pandemic, and underline the need for low-threshold mental health support.