Objective: Obsessive-compulsive disorder is characterized by a chronic course that can vary between patients. The knowledge on the naturalistic long-term outcome of obsessive-compulsive disorder and its predictors is surprisingly limited. The present research was designed to identify clinical and psychosocial predictors of the long-term outcome of obsessive-compulsive disorder. Methods: We included 377 individuals with a current diagnosis of obsessive-compulsive disorder, who participated in the Netherlands Obsessive Compulsive Disorder Association study, a multicenter naturalistic cohort study. Predictors were measured at baseline using self-report questionnaires and clinical interviews. Outcome was assessed using the Yale-Brown Obsessive Compulsive Scale at 2-, 4- and 6-year follow-up. Results: The overall course of obsessive-compulsive disorder was characterized by two prominent trends: the first reflected an improvement in symptom severity, which was mitigated by the second, worsening trend in the long term. Several determinants affected the course variations of obsessive-compulsive disorder, namely, increased baseline symptom severity, late age of onset, history of childhood trauma and autism traits. Conclusion: The long-term outcome of obsessive-compulsive disorder in naturalistic settings was characterized by an overall improvement in symptom severity, which was gradually halted to the point of increased worsening. However, after 6 years, the severity of symptoms remained below the baseline level. While certain determinants predicted a more favorable course, their effect diminished over time in correspondence to the general worsening trend. The results highlight the importance of a regular and continuous monitoring for symptom exacerbations as part of the management of the obsessive-compulsive disorder, regardless of the presence of putative predictors.