Background: Individuals with depression have a higher risk of Parkinson's disease (PD) but the timing of the association is unknown. Therefore, the relationship between initiation of antidepressant therapy and PD risk was assessed in a large population based database from the UK and the timing of this association was explored. Methods: A case control study nested in the General Practice Research Database cohort, a large computerised database with clinical information from more than 3 million individuals in the UK, was conducted. Cases of PD were identified from the computer records from 1995 to 2001 and matched with up to 10 controls by age, sex and practice. Use of antidepressants was obtained from the computer records. Results: 999 PD cases and 6261 controls were included. The rate ratio (RR) and 95% CI of PD in initiators of antidepressant therapy compared with non-initiators was 1.85 (1.25 to 2.75). The association was stronger during the first 2 years after initiation of medication use (RR 2.19; 95% CI 1.38 to 3.46) than later (RR 1.23; 95% CI 0.57 to 2.67). Results were similar for selective serotonin reuptake inhibitors and tricyclic antidepressants separately. Conclusion: Initiation of any antidepressant therapy was associated with a higher risk of PD in the 2 years after the start of treatment, which suggests that depressive symptoms could be an early manifestation of PD, preceding motor dysfunction.