Background: Psychiatric evaluation of adults with intellectual disability (ID) remains complex because of limitations in verbal abilities, atypical clinical presentation and challenging behaviour. This study examines the clinical presentation of adults with depression compared with bipolar disorder, anxiety disorders and non-psychiatric control patients. Method: This study is a retrospective record review of the initial psychiatric diagnostic evaluation for 300 adult patients with ID drawn from a clinic population. Patients with major depression (n = 85) were compared with those with bipolar disorder (n = 70), anxiety disorders (n = 30) and control patients without psychiatric disorder (n = 27). Key symptoms of depression assessed during the interview were examined as well as challenging behaviour. Results: Three symptoms were useful in differentiating depressed patients from all other groups: sad mood, crying, and anhedonia. Withdrawal, suicidality, and awakening during the night were significant compared with anxiety patients and controls; however, few patients reported suicidality. Bipolar patients were significantly different from depressed patients for elevated mood, acute anger episodes, increase in verbalization, pressure of speech, talk of sexual themes, increase in appetite and poor concentration. Anxiety patients had more fearfulness without withdrawal, sad mood, crying, anhedonia and suicidality. Challenging behaviour was most pronounced in bipolar patients; for depressed patients, aggression and impulsivity were significant compared with anxiety patients and controls. Overall, the control patients presented with few symptoms in any category. Conclusions: Sad mood, crying and anhedonia are key significant features of depression. Most patients with ID cannot meet the required number of DSM criteria or suggested DM-ID adapted criteria for major depression. Many depressive symptoms were reported in modest numbers and this was probably related to deficiencies in self-report or observational skills of caregivers. Challenging behaviour is not diagnostically specific. It is, however, a key atypical feature of depression.