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Little is known about factors that affect health-related quality of life during the early follow-up of colorectal cancer. This study was designed to identify the factors that contribute to poor health-related quality of life after six weeks of follow-up and to compare the relative performance of instruments best suited to measure it.A single-center, prospective study was designed to examine health-related quality of life after potentially curative surgery for colorectal cancer. Two condition-specific and two generic instruments (QLQ-C30, FACT-C, SF12 and EQ-5D) measured quality of life six weeks after discharge. Univariate and multivariate analyses were used to assess the impact of 16 treatment factors, demographic variables, and symptoms on seven global health-related quality of life scores.Questionnaires were obtained from 201 consecutive patients. Five factors were associated with poor health-related quality of life scores at six-week follow-up in the multivariate analysis: reduced preoperative performance status, stomas, diarrhea, constipation, and younger than aged 65 years. No instrument out performed the others. However, condition-specific instruments and those in which patients subjectively rated their overall health-related quality of life were better suited to detect health-related quality of life differences relating to the effects of colorectal cancer treatment.Younger patients, those with stomas, and those suffering from diarrhea or constipation are more likely to report poor health-related quality of life at six-week follow-up. The routine measurement of health-related quality of life using an instrument that includes a patient-rated scale together with condition-specific items could be used to detect patients at risk of poorer short-term health-related quality of life outcomes.