OBJECTIVES: Low-grade systemic inflammation may contribute to the development of depression. We tested the hypothesis that elevated plasma levels of the inflammatory marker fibrinogen are associated with psychological distress, use of antidepressant medication, and with hospitalization with depression in the general population. METHODS: We examined 73,367 20-100 year old men and women from two large population-based studies, the Copenhagen General Population Study and the Copenhagen City Heart Study. We measured plasma fibrinogen and recorded symptoms of psychological distress, use of antidepressant medication, and hospitalization with depression in both cross-sectional and prospective studies. RESULTS: In cross-sectional analyses, a stepwise increase in fibrinogen percentile categories was associated with a stepwise increase in risk of psychological distress, use of antidepressant medication, and hospitalization with depression (p-trend 2×10(-11) to 5×10(-95)). Furthermore, when different classes of antidepressant medication were examined, a stepwise increase in fibrinogen percentile categories was associated with a stepwise increase in risk of use of Selective Serotonin Reuptake Inhibitors and Tricyclic Antidepressants (p-trend 7×10(-18) and 6×10(-7), respectively). In prospective analyses, stepwise increasing fibrinogen percentile categories also associated with stepwise increasing risk of hospitalization with depression (p-trend=7×10(-6)): age and gender adjusted hazard ratios were 1.13 (95% confidence interval 0.70-1.83) for the 25.1-50th percentiles, 1.53 (0.97-2.42) for the 50.1-75th percentiles, 1.82 (1.11-2.97) for the 75.1-90th percentiles, 2.10 (1.12-3.95) for the 90.1-95th percentiles, and 3.23 (1.79-5.85) for the >95th percentiles, versus the 0-25th percentiles. CONCLUSION: Elevated levels of fibrinogen were associated with psychological distress, use of antidepressant medication, and with hospitalization with depression in 73,367 individuals from the general population, in cross-sectional studies and in prospective studies for hospitalization with depression.