Interpretation of change over time in patient-reported outcomes requires appropriate responder definitions. This study compares responder definitions for the short-form version of the Quality of Life Enjoyment and Satisfaction Questionnaire [Q-LES-Q(SF)] in populations with generalized anxiety disorder (GAD) and bipolar disorder. A review of the Q-LES-Q(SF) literature published in English from 1993 through May 2009 identified publications using the Q-LES-Q(SF) in GAD or bipolar disorder clinical trials. In six relevant articles reporting Q-LES-Q(SF) responder definitions in GAD or bipolar disorder, two methods for defining responders emerged: (i) return to a score within 10% of community norms for the Q-LES-Q(SF); and (ii) a change score at or greater than the condition-specific mean change achieved by patients with minimal improvement on the Clinical Global Impression–Improvement (CGI-I) at study endpoint or a 1-point decrease on the CGI–Severity scale between baseline and study endpoint. The magnitude of the CGI-I based responder thresholds differed across mental health conditions. Use of the Q-LES-Q(SF) community norms as a responder definition is discouraged. A responder definition needs to be investigated within each condition or disease using appropriate anchors, and may not be generalizable from one condition or disease to another.