Purpose The aim of this study was to identify symptoms of severe intensity or very low scores for quality of life (QoL) domains in newly diagnosed outpatients with advanced cancer. Methods This multicenter cohort study from a state-wide palliative care network included adult outpatients with advanced cancer diagnosed within the preceding 8 weeks from four comprehensive cancer centers (DRKS00006162, registered on 19 May 2014). We used the Palliative Outcome Scale (POS), Hospital Anxiety and Depression Scale, and European Organization for Research and Treatment of Cancer QoL Questionnaire-C30. For each questionnaire, cut-off scores defined symptoms and QoL domains that were considered "severe" or "very low." Results Of 3155 patients screened, 481/592 (81.3%) were analyzed (mean age 62.4; women n = 245, 50.9%). We identified 324/481 (67.4%) patients experiencing at least one severe symptom or a very low QoL domain (median 2; range 0 to 16). Role functioning (n = 180, 37.4%), fatigue (n = 162, 33.7%), and social functioning (n = 126, 26.2%) were most commonly affected. QoL was very low in 89 patients (18.5%). Women experienced more anxiety symptoms, fatigue, and had lower POS scores. Patients often mentioned physical symptoms and fears of adverse events resulting from disease-modifying therapies (e.g., chemotherapy) as most relevant problems. Conclusions Already within the first 8 weeks after diagnosis, the majority of patients reported at least one severe symptom or a very low QoL domain. Gender differences were evident. The findings illustrate the value of early routine assessment of patient burden and the development of multi-professional and interdisciplinary palliative care.