To evaluate the relationship between personality and emotional distress in prostate cancer. Neuroticism and introversion were hypothesized to be associated with clinically significant symptoms of emotional distress, including depression, anxiety, and suicidal ideation. Men with a history of prostate cancer (n=212) completed an NIH-funded cross-sectional study using well-validated measures of personality, depression, anxiety, and suicidal ideation. Covariates were age, education, time since diagnosis, comorbidity, and presence of metastases. Emotional distress was reported by 37% of participants, including depression (23%), anxiety (15%), and suicidal ideation (10%). As hypothesized, men who were more neurotic were more likely to report emotional distress (44.5% vs 26.9%; OR=2.78, P=.004), depression (31.9% vs 11.8%; OR=4.23, P=.001), and suicidal ideation (29.4% vs 9.7%; OR=4.15, P=.001). Introverts were more likely to report emotional distress (45.2% vs 28.7%; OR=2.32, P=.012) and depression (30.8% vs 15.7%; OR=2.57, P=.014). Men with metastases were more likely to report emotional distress (51.7% vs 31.2%; OR=4.56, P<.001). Neuroticism and introversion were associated with clinically significant emotional distress in men with prostate cancer. Findings suggest that, in the context of treatment for prostate cancer, patient distress reflects disease characteristics (eg, metastases presence) as well as stable personality traits. Implications for clinical care are discussed.