Objective.The purpose of this study was to compare the sensitivity of four generic effectiveness measures with clinically meaningful symptom improvement in persons with schizophrenia.Method.Baseline and 6-month interviews were conducted with 134 subjects diagnosed with schizophrenia or schizoaffective disorder. The design was observational. The four generic effectiveness measures included the Quality of Well-Being scale (QWB), a quality-adjusted index score based on the SF-36 VAS, Veterans SF-36 mental health component summary score (MCS), and the World Health Organization Disablement Assessment Schedule (WHO-DAS). Symptom measures included the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale (CDS). The side effect measure was the Extrapyramidal Symptom Rating Scale (ESRS). Data analysis included correlations between symptom, side effect, and generic effectiveness change scores; and an effect size calculation to detect a clinically significant improvement in the total PANSS.Results.All four effectiveness measures were correlated with changes in side effects. All but the SG-36 VAS were correlated with changes in depression. Only the QWB was correlated with changes in PANSS scores. The QWB required at least three times fewer subjects (n = 61) to detect a clinically significant improvement in total PANSS compared with the other effectiveness measures (n = 201–324).Conclusions.It is recommended that clinicians and researchers use the QWB to demonstrate the effectiveness and cost-effectiveness of schizophrenia interventions. The QWB allows for direct comparison of the effectiveness and cost-effectiveness of schizophrenia interventions with other mental and physical health interventions and may contribute to a greater recognition of the value of mental health interventions.