Objectives: The primary objective in this study is to determine the sensitivity and specificity of a two-item screening interview for depression versus the formal psychiatric interview, in the setting of a specialist palliative in-patient unit so that we may identify those individuals suffering from depressive disorder and therefore optimise their management in this often-complex population. Methods: A prospective sample of consecutive admissions (n = 167) consented to partake in the study, and the screening interview was asked separately to the formal psychiatric interview. Results: The two-item questionnaire, achieved a sensitivity of 90.7% (95% Cl 76.9-97.0) but a lower specificity of 67.7% (95% Cl 58.7-75.7). The false positive rate was 32.3% (95% Cl 24.3-41.3), but the false negative rate was found to be a low 9.3% (95% Cl 3.0-23.1). A subgroup analysis of individuals with a past experience of depressive illness, (n=95), revealed that a significant number screened positive for depression by the screening test, 55.2% (16/29) compared to those with no background history of depression, 33.3% (22/66) (P=0.045). Conclusion: The high sensitivity and low false negative rate of the two-question screening tool will aid health professionals in identifying depression in the in-patient specialist palliative care unit. Individuals, who admit to a previous experience of depressive illness, are more likely to respond positively to the two-item questionnaire than those who report no prior history of depressive illness (P=0.045).