To examine the responsiveness of generic and condition-specific instruments based on the anchor of self-reported level of global change in patients with colorectal cancer (CRC).Three hundred thirty-three patients with CRC were surveyed at two assessments at baseline and follow-up at 6 months from September 2009 to July 2010 using the Short Form-12 Health Survey version 2 (SF-12v2) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C) measures. The responsiveness of the two measures was evaluated using standardized effect size, standardized response mean, responsiveness statistic, and receiver operating characteristic (ROC) curve analysis.In worsened group, internal responsiveness of detecting negative changes was satisfactory for most subscales of FACT-C and SF-12v2. The FACT-C subscales were significantly more responsive to positive changes detection than the SF-12v2 subscales in improved group. Physical well-being subscale, Trial Outcome Index (TOI), and total score of FACT-C were more externally responsive to ROC curve analysis. The FACT-C measure was generally more responsive to changes in health status compared with SF-12v2 measure.TOI and total score of FACT-C were the most responsive among subscales of condition-specific measure, which were more responsive than all generic subscales with the exception of social domain. Complementary use of condition-specific and generic instruments to evaluate the health-related quality of life of CRC patients is encouraged.