Mental health problems are highly prevalent in primary care. Validated tools to detect mental disorders in general practice are needed. The Four-Dimensional Symptom Questionnaire (4DSQ) was designed to help GPs differentiating between psychological distress and psychopathological conditions (depression, anxiety, somatization). The aim of the current study was to examine psychometric properties of the 4DSQ in a mental health setting. Reliability, factorial, construct, and criterion validity of the English translation of the 4DSQ were analyzed in an American sample of 159 patients attending a psychotherapy outpatient clinic. Measurement equivalence across languages was determined by analyzing differential item functioning (DIF) and differential test functioning (DTF) in the American sample and a Dutch mental health sample, matched by age and sex. A confirmatory factor analysis confirmed all 4DSQ subscales to be unidimensional. All 4DSQ subscales revealed excellent reliability (Cronbach's alpha and McDonald omega ≥.90) and high correlations with a symptom distress subscale of an instrument that is commonly used to monitor psychotherapy progress, the Outcome Questionnaire-45. Eight items were flagged with DIF. The Depression subscale was free of DIF. DTF analyses showed an impact of DIF on scale level for the lower cutoff score of the Distress scale. The 4DSQ Distress score was the best predictor of a mood disorder diagnosis and the Anxiety score outperformed other 4DSQ scales to predict an anxiety disorder. In conclusion, the 4DSQ demonstrates excellent reliability and validity in a mental health setting. Further research is needed to determine reliable cutoff values on 4DSQ subscales to predict psychiatric diagnoses.