The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I<O before chemotherapy independently predicted overall survival. This study investigates the relevance of I<O measured during chemotherapy for survival and symptoms. The circadian rest-activity pattern was monitored for 3 days using a wristwatch actigraph while 77 patients were receiving a chemotherapy course within an international randomized Phase III trial. Treatment consisted of first-line chronomodulated or conventional delivery of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer. I<O was computed as the percentage of minutes of activity counts in bed which were below the median of activity out of bed. Circadian disruption was defined by I<O equal to or less than 97.5%. Circadian disruption occurred in 39 patients (51%) on chemotherapy. It was associated with a significantly shorter overall survival, independently of other prognostic factors (multivariate Hazard Ratio: 2.12; p = 0.004). The median survival of patients with a robust circadian rhythm was 22.3 months as compared to 14.7 months in those with circadian disruption during chemotherapy. No toxicity was significantly associated with circadian disruption, but the incidence of grade ≥2 fatigue and of body weight loss ≥5% was two and threefold higher, respectively, in patients with disrupted circadian rhythm on chemotherapy. Chemotherapy disrupted circadian activity rhythm in nearly 50% of the patients. Circadian disruption on chemotherapy predicted for shorter overall survival. The prevention of chemotherapy-induced circadian disruption might reduce toxicity and improve efficacy in cancer patients.