Assessment of psychological distress is important, because it may help to monitor treatment effects and predict treatment outcomes. We previously developed the 48-item Symptom Questionnaire (SQ-48) as a public domain self-report psychological distress instrument and showed good internal consistency as well as good convergent and divergent validity among clinical and non-clinical samples. The present study, conducted among psychiatric outpatients in a routine clinical setting, describes additional psychometric properties of the SQ-48. The primary focus is on responsiveness to therapeutic change, which to date has been rarely examined within psychiatry or clinical psychology. Since a questionnaire should also be stable when no clinically important change occurs, we also examined test–retest reliability within a test–retest design before treatment (n = 43). A pre-treatment/post-treatment design was used for responsiveness to therapeutic change, comparing the SQ-48 with two internationally widely used instruments: the Brief Symptom Inventory (n = 97) and the Outcome Questionnaire-45 (n = 109). The results showed that the SQ-48 has excellent test–retest reliability and good responsiveness to therapeutic change, without significant differences between the questionnaires in terms of responsiveness. In sum, the SQ-48 is a psychometrically sound public domain self-report instrument that can be used for routine outcome monitoring, as a benchmark tool or for research purposes.