There is conceptual overlap between negative and depressive symptoms: Mainly the ‘avolition’ factor of negative symptoms also encompasses main symptoms of depression. However, whereas in depression mood is low, mainly anticipatory anhedonia can be found in negative symptoms. Moreover, patients with schizophrenia (SCZ) show greater expressive deficits than those with Major Depressive Episode (MDE). We investigated if measures of depressive and negative symptoms differentiate SCZ subjects, subjects with MDE, and healthy controls (HC). 21 SCZ, 22 MDE, and 25 HC subjects were examined with a rater assessment and a self-rating for negative symptoms (Clinical Assessment Interview for Negative Symptoms (CAINS); Motivation and Pleasure – Self-Report (MAP-SR)) and depressive symptoms (Hamilton Rating Scale for Depression (HAMD-17); Beck Depression Inventory (BDI)). All measures differentiated the psychiatric samples from HC (all p’s < 0.01). The ratings of depressive symptoms (HAMD-17, BDI) and rater assessment of negative symptoms (CAINS) – specifically its sub scale measuring expressive deficits – managed to discriminate between subjects with schizophrenia and those with MDE (SCZ > MDE > HC for negative, MDE > SCZ > HC for depressive symptoms, all p’s < 0.05). The self-rating of negative symptoms (MAP-SR) did not. To differentiate negative symptoms and depression clinicians might look for (self-)reported low mood and observer-rated reduction in speech as well as in gestures and facial expression. Reduced expression and moderate levels of depression point towards a negative syndrome, whereas mostly unimpaired expression and high scores of self-reported depressive symptoms are more likely to indicate a depressive syndrome.