OBJECTIVE To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC). METHODS Patients (N = 18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100 mg/m(2) on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000 mg) once daily taken at 2400 hours on days 1-5. Each cycle lasted 14 days. RESULTS The MTD of capecitabine was 4,500 mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3 %, and median overall survival was 16.3 months (95 % CI: 11.2-18.2 months). The maximum plasma concentration (C(max)) and area under plasma concentration-time curve from time 0 to infinity (AUC([0-∞])) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity. CONCLUSIONS Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.