Approximately 28% of patients with gastrointestinal (GI) cancers will receive targeted therapy (TT) because of the associated increases in survival. Only four studies have examined the symptom experience of these patients. To date, no studies have evaluated for differences in symptom occurrence, severity, and distress between patients who received chemotherapy (CTX) alone (n=304) or CTX with TT (n=93).Patients completed self-report questionnaires, approximately one week after they received CTX. A modified version of the Memorial Symptom Assessment Scale (MSAS) was used to obtain data on symptom occurrence, severity, and distress. Binary logistic regression analyses were used to test for differences in symptom occurrence rates between the two treatment groups. Ordinal logistic regression analyses were used to test for differences in severity and distress ratings between the two treatment groups.Patients who received CTX with TT were significantly younger (P=0.009); were diagnosed with cancer longer (P=0.004); had a higher number of prior treatments (P=0.024); had metastatic disease, specifically to the liver (P<0.001); had a diagnosis of anal, colon, rectum, or colorectal cancer (CRC) (P<0.001); and were positive for detection of B-Raf proto-oncogene, serine/threonine kinase (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (both P<0.001). In addition, CTX treatment regimens were significantly different between the two groups (P<0.001). After controlling for significant covariates, patients who received TT reported lower occurrence rates for lack of energy, cough, feeling drowsy, and difficulty sleeping (all, P<0.05). Patients who received TT reported lower severity scores for dry mouth (P=0.034) and change in the way food tastes (P=0.035). However, they reported higher severity scores for "I don't look like myself" (P=0.026). No differences in symptom distress scores were found between the two treatment groups.This study is the first to evaluate for differences in the symptom experience of GI cancer patients who received CTX alone or CTX with TT using a multidimensional symptom assessment scale. While between group differences in patients' symptom experiences were identified, both treatment groups warrant ongoing assessments to optimally manage their symptoms.