Purpose: Cancer patients may experience an array of issues that cause distress. While substantial energy is invested in preparing patients for distress associated with treatment risks and possible side effects, little is overall known about the causes, prevalence, and clinical impact of distress on treatment outcomes. The purpose of this study was to identify which stressors (practical, emotional, familial, or physical) are most strongly associated with distress. We also assessed associations between distress and clinical trial outcomes. Methods: Validated measures were used for baseline assessments of distress (NCCN-DT), anxiety (HADS-A), and depression (HADS-D) on patients beginning a Phase I trial. The NCCN Problem List was used to evaluate the frequency of specific stressors including: practical (e.g. insurance/financial), family (e.g. family health issues), emotional (e.g. nervousness), or physical (e.g. fatigue). Adverse events on trial including hospitalizations, toxicities, or death of the participants were collected prospectively. Pearson’s product moment correlation tested the relationship between distress and HADS-A and HADS-D. Spearman’s rank correlation tested the relationship between distress and the NCCN Problem List categories. Results: Baseline assessments were conducted on 87 participants (45F/42M; mean age 60 yrs) enrolling on Phase I trials at Fox Chase Cancer Center. Mean number of previous therapies was 2. Among participants, 54% reported distress, 28% anxiety, and 21% depression. There was a positive correlation between distress and anxiety (r = 0.47, p < 0.001) and a trend towards significance with depression (r = 0.20, p = 0.06). The most commonly reported items from the NCCN-DT were worry (49%), fatigue (37%), pain (31%), sleep (31%), fears (30%), and nervousness (30%). A positive correlation was found between distress and practical stressors (r = 0.31, p = 0.02) and distress and emotional stressors (r = 0.64, p < 0.001). Of note, there was no significant correlation between distress and physical stressors (r = 0.17, p = 0.2). No significant associations were found between distress and clinical trial outcomes. Conclusions: Distress was prevalent among participants in Phase I clinical trials, but did not negatively impact trial outcomes. Emotional and practical stressors were associated with higher levels of distress, while, somewhat surprisingly, physical stressors were not.