As survival of metastatic colorectal cancer (mCRC) increases, patients have more exposure to chemotherapy and related toxicity. The objective is to determine how toxicity patterns affect care. Via a population-based strategy, mCRC cases diagnosed between June 2003 and June 2006 were identified from one academic and nine community oncology practices in the southeastern United States. Demographic, disease, treatment, hospitalization, and toxicity data were abstracted by retrospective chart review, double-entered, and verified for accuracy. Of the 738 charts screened, 110 were eligible based upon preidentified inclusion criteria. As part of first-line chemotherapy, 87% received oxaliplatin, 12% received irinotecan, and 74% received bevacizumab. Gastrointestinal toxicity was the most common toxicity-related cause of drug discontinuation (16 of 61 events) and hospitalization (19 of 54 events). Both neurologic and hematologic toxicities were identified more frequently when oxaliplatin-containing regimens were administered (50% and 48%, respectively) than with irinotecan-containing regimens (10% and 24%, respectively). Dose reduction was most commonly associated with hematologic toxicity (22 of 55 events). Oxaliplatin and irinotecan required similar rates of antidiarrheal, antinausea, erythropoiesis-stimulating, and granulocyte-stimulating treatments. These data, obtained from a usual-practice setting, provide benchmarks to improve clinical practice.