<b><i>Background:</i></b> Antidepressant use is highly prevalent. Research has mainly focused on efficacy during short periods of use for depression and anxiety. There is a relative paucity of data regarding the frequency of long-term use. <b><i>Methods:</i></b> To determine the prevalence and possible increase of long-term use of antidepressants over recent years, we analyzed routine general practice care data in a large cohort of patients (<i>n</i> = 156,620) in and around Amsterdam, The Netherlands. Additionally, predictors of long-term use were studied. <b><i>Results:</i></b> Prevalence of long-term use of antidepressants is substantial, and such use appears to be increasing: 30.3% of use was long-term over the period 1995-2005 compared to 43.7% for the period 2005-2015. Higher age, a registered diagnosis of anxiety or depression, and the use of SSRIs or SNRIs were associated with long-term use in multivariate analysis. In addition, specific antidepressants were differentially associated with long-term use. <b><i>Conclusions:</i></b> Long-term antidepressant use is substantial and appears to be on the rise. Awareness of this phenomenon should be increased, such use should be prevented when possible, and reasons for long-term use need to be examined.