OBJECTIVE: A new patient-reported outcome (PRO) measure developed to assess the impact of major depressive disorder (MDD) on partner and family interactions and quality of relationships, the Depression and Family Functioning Scale (DFFS), was analyzed to establish its reliability, validity, and responsiveness. METHODS: Data from a multi-center, prospective, 2-year observational study were analyzed to assess the psychometric properties of the DFFS in patients with MDD (nBaseline = 478; nMonth2 = 433). Measures administered to assess validity included the Sheehan Disability Scale (SDS), Arizona Sexual Experiences Scale (ASEX) and Short Form Health Survey-12 (SF-12). Reliability (Cronbach’s alphas and intra-class correlations), construct validity (factor analysis and correlations), discriminating ability (analyses of variance), and responsiveness (standardized effect size estimates) were evaluated. RESULTS: Principal components analyses indicated a single underlying dimension, confirmed by highly satisfactory Cronbach’s alphas (alphaBaseline = 0.85, alphaMonth2 = 0.89). The DFFS demonstrated satisfactory test-re-test reliability in patients with the same SDS family life/home responsibilities ratings at baseline and month 2 (intraclass correlation = 0.75). Correlations with other measures showed convergent and divergent validity; e.g., the DFFS correlated better with SF-12 mental component scores (rBaseline = -0.35, rMonth2 = -0.49) than with SF-12 physical component scores (rBaseline = -0.05, rMonth2 = -0.31). Hypothesis tests were generally as predicted; many were statistically significant, substantiating DFFS discriminating ability. Standardized effect size estimates of responsiveness ranged from 0.44-0.84, demonstrating that the items were capable of detecting change. CONCLUSIONS: The psychometric analyses support the reliability, validity, and responsiveness of the DFFS and its usefulness for assessing the impact of depression on family functioning. The DFFS can potentially provide important information not captured in clinical practice and facilitate more comprehensive evaluation of MDD treatments.