Background: Information on the natural course of subthreshold depression and risk factors for the development of a full-blown depressive disorder in the general population is scarce. This information is crucial to understand the development of depression and to advance indicated depression prevention. Methods: Using longitudinal data from a representative population-based study (the Netherlands Mental Health Survey and Incidence Study-2) we assessed 3-year course of subthreshold depression (depressive symptoms causing clinically significant distress for at least 2 weeks, or for 3 days per month for a year; n = 120), compared to an asymptomatic group (n = 4111) and a depressive disorder group (major depression or dysthymia; n = 294). Next, risk factors for the development of a depressive disorder among adults with subthreshold depression were determined. Results: Twelve percent of the subthreshold cases developed a full-blown depressive disorder during 3-year follow-up. Risk factors were lower social support, having recurrent short episodes of depressive symptomatology, remitted and current anxiety disorder, remitted substance use disorder, lifetime suicide thoughts, a chronic physical disorder and diminished mental and physical functioning. Limitations: The number of subjects with subthreshold depression that developed a depressive disorder was small. This limits the possibility to detect significant risk factors. Conclusion: Only a minority of the subthreshold cases developed a full-blown depressive disorder over three years. This shows that subthreshold depression does not, by itself, carry an a priori risk to warrant focusing indicated prevention. The identified risk factors could help to detect those subthreshold cases in whom depression prevention is economically and practically viable.