Introduction: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) co-occur at high rates, often preceding and predicting one another over long durations. Interpersonal theories propose that relationships with others may mediate the longitudinal MDD–GAD pathway. Therefore, the current study examined the mediational effect of positive relations with others over 18 years. Methods: Community-dwelling adults (n = 3,294) completed self-reports at three time-points, each spaced about nine years apart. GAD and MDD symptoms (Composite International Diagnostic Interview–Short Form) were assessed at Time 1 (T1) and Time 3 (T3). The level of positive relations (Psychological Well-Being Scale–Positive Relations with Others) was measured at Time 2 (T2). Structural equation mediation modeling was used for data analysis. Results: Results indicated that T2 positive relations with others significantly mediated the relationship between more severe T1 GAD symptoms and elevated T3 MDD severity (d = 0.36), accounting for 12.2% of the variance of this connection. T2 positive relations with others also mediated the association between higher T1 MDD severity positively predicting more severe T3 GAD symptoms (d = 0.38) and explained 10.7% of the variance. All indirect effects of T2 positive relations with others in the 18-year MDD-GAD pathway were significant after adjusting for age, gender, education, and baseline symptoms (d = 0.20¬–0.37). Conclusions: Supporting interpersonal theories, lack of positive relationships with others mediated the 18-year bidirectional connections between GAD and MDD symptoms. Cognitive-behavioral therapies could be augmented by incorporating strategies that enhance interpersonal functioning and perceived social support.