OBJECTIVE: To determine the validity of a 50% drop in the 20-item Symptom Checklist Depression Scale (SCL-20) score against the "gold standard" of no longer meeting criteria for major depression as assessed using a diagnostic interview in an outpatient cancer population and also to examine the validity of other potential cut-offs (i.e., percentage drops). MATERIALS AND METHODS: Secondary analysis of data from a randomized trial which compared collaborative care with usual care for cancer patients with major depression. A total of 194 trial participants who had both SCL-20 scores and depression diagnoses on the Structured Clinical Interview for DSM-IV at both baseline and at 12-week outcome formed the analyzed sample. RESULTS: A 50% reduction in the SCL-20 score from baseline to 12 weeks correctly identified the patients who no longer met criteria for major depression in 153 (78.9%) of 194 (95% CI 73.1% to 84.6%) cases. Most of those misclassified had not achieved a 50% reduction in SCL-20 score despite no longer meeting criteria for major depression. Examination of the performance of percentage drops other than 50% on the SCL-20 using a receiver operating characteristics (ROC) curve and histogram of misclassification suggested that the 50% drop was best if both a low overall misclassification rate and the minimizing of false positives of improvement were required. CONCLUSIONS: A 50% reduction in the SCL-20 score performs well as a conservative measure of change in depression status in cancer patients.