Purpose <p>To investigate patterns of weight change during chemotherapy for colorectal cancer and analyse their associations with patient demographic, clinical factors, and health-related quality of life (HRQoL).</p> Methods <p>We performed secondary analysis of data from 2,871 participants of the SCOT randomised controlled trial. SCOT compared 3&#xa0;months to 6&#xa0;months of adjuvant oxaliplatin-containing chemotherapy in people with colorectal cancer. HRQoL was measured with EQ-5D-3L. Mean changes in weight over time were plotted with 95% confidence intervals (CIs) and analysed stratified by sex, chemotherapy regimen and duration. Associations with patient characteristics were evaluated using multivariable linear regression.</p> Results <p>The median age of participants was 65 (interquartile range was 59 to 70), 38.7% were female and 95.8% of participants were white. Male participants gained on average 1.2&#xa0;kg (95% CI 1.0 to 1.4), and females gained 0.8&#xa0;kg (95% CI 0.6 to 1.1). By the end of treatment, 161 (6.1%) participants shifted from body mass index (BMI) &lt; 25&#xa0;kg/m² (healthy range) to ≥ 25&#xa0;kg/m² (overweight and obese), and 73 (2.7%) from BMI ≥ 25 to BMI &lt; 25&#xa0;kg/m², <i>p</i> &lt; 0.001. Furthermore, 210 (7.3%) participants experienced weight loss of more than 5% of their body weight, while 560 (19.5%) gained more than 5%. Change in body weight was associated with age (per 10-year increase -1.9, 95% CI -2.4 to -1.4), male sex (1.6, 95% CI 0.7 to 2.5), and the HRQoL health index (0.6, 95% CI 0.2 to 0.9), all <i>p</i> &lt; 0.001.</p> Conclusions <p>Younger patients, males, and those with higher HRQoL experienced greater weight gain during chemotherapy for colorectal cancer, emphasising the need to monitor and manage body weight to prevent increase in obesity during curative treatment.</p>