The present study examined the predictive validity of Cluster C personality disorders (CCPDs) on major depressive disorder (MDD), using Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, N = 34,653; time interval equals 3 years). Multiple logistic regression analyses were utilized to compare respondents with MDD and a concurrent CCPD to those with MDD only. Findings demonstrated that individuals with MDD and a comorbid CCPD were significantly more likely than those with MDD only to have MDD at Time 2. The presence of comorbid CCPD in individuals with MDD also predicts the subsequent occurrence of suicide attempts at Time 2 and the new onset of Axis I anxiety disorders. The chronic and enduring personality styles and interpersonal difficulties that characterize individuals with a CCPD likely lead to the exacerbation of MDD symptoms. Clinicians should be aware of the impact that CCPDs have on the outcome of MDD.