Background: The large between-person differences in symptomatology suggest that major depressive disorder (MDD) is a heterogeneous psychiatric disorder. However, symptom-specific prospective studies are scarce. We hypothesized that chronicity (i.e., being depressed for 24 months during a patient's preceding 48 months at baseline) and neuroticism at baseline would predict adverse course trajectories over 9 years of follow up with differential magnitudes for individual depressive symptoms. Methods: In total, 560 patients with a current MDD were included from the Netherlands Study of Depression and Anxiety (NESDA-cohort). We used a multivariate linear mixed model with repeated measures, with a history of chronicity and neuroticism separately as main independent variables and with Inventory of Depressive Symptomatology self-report (IDS-SR) item scores as outcome variables. For each individual symptom, the model was adjusted for age, gender, and baseline depression severity. Results: Patients were on average 42.7 (SD = 12.1) years old and 64.7% were women. Patients with chronic depression or high levels of neuroticism showed similar absolute rates of decline over time compared to their counterparts. However, because symptoms had higher starting points for mood, cognitive, and somatic/vegetative symptoms (in that order), symptom severity remained higher over time. Chronicity and neuroticism were especially linked to persistent low self-esteem and high interpersonal sensitivity. Limitations: Neuroticism is partly state dependent and likely affected by depression severity. Conclusions: Chronicity and neuroticism predict long-term persistence of diverse psychiatric symptoms, in particular low self-esteem and high interpersonal sensitivity.