Background: Few data exist on patient-reported outcomes, specifically symptoms, in patients with advanced cancer who seek or are in treatment in phase I clinical trials of molecular targeted agents (phase I patients). We explored patient clusters based on symptom severity, and examined associated factors. Methods: Phase I patients completed the validated core MD Anderson Symptom Inventory (with 13 symptom and 6 symptom interference items, each rated on a 0-10 scale) and the Profile of Mood States. ECOG performance status was assessed. Cluster analysis was used. Results: In phase I patients (N = 248, 51% female, 90% ECOG 0-1, and 52% ≥ 60y), symptoms with highest reported mean severity were fatigue (4.6), drowsiness (3.7), pain (3.6), and lack of sleep (3.0). Highest symptom-related interference was with work (3.5), activity (3.4), and enjoyment of life (3.4). Two natural patient clusters based on reported symptom severity were seen: 38% of patients were in the high symptoms cluster (HSC), and 62% were in the low symptoms cluster (LSC). HSC patients reported greater tension, depression, anger, confusion and lower vigor (p < 0.001), were more likely to have poor PS (ECOG > = 2) (16.5% vs. 4.7%, p < 0.003) and reported higher symptom-related interference (5.1 vs. 1.8, p < 0.001) than LSC patients. Cluster membership did not vary by current enrollment on a phase I clinical trial (p > 0.05) or by the number of cycles completed (6.8 vs. 6.4 cycles, p > 0.05). Patients on a phase I trial reported less dyspnea (1.0 vs. 1.95, p < 0.001) and vomiting (0.53 vs. 1.07, p < 0.029) than patients not enrolled, but did not differ in other symptoms. Patients < 60y of age on a trial were more likely to be in the HSC than patients ≥ 60 y (60% vs. 41%, p < 0.038). Conclusions: Patient-reported symptoms, particularly fatigue, drowsiness, pain and lack of sleep should be routinely assessed in phase I clinics, potentially improving attribution of adverse events. Also, current enrollment on a phase 1 trial does not appear to adversely impact symptoms. Treatment of symptoms may include counseling, especially for younger patients, given their higher reported symptom severity. Patient-reported outcomes can complement physician assessment to enhance treatment plans.