The objective of this study was to investigate whether polymorphisms in the ABCB1 gene were associated with switching, with discontinuation of antidepressants within 45 days after starting therapy, and/or with dose change in a large prospective population-based cohort study. Between April 1, 1991, and December 31, 2007, there were 1257 incident users of antidepressants with known ABCB1 genotypes ( 1236C>T, 2677G>T/A, 3435C>T) in the population-based Rotterdam Study. Logistic regression models were used to estimate the genotype and haplotype effect on the risk of switching and discontinuation. In addition, the association between the haplotypes and the prescribed drug dosage was assessed per drug class. The separate polymorphisms in the ABCB1 gene were associated with increased risks of switching and discontinuation but reached only statistical significance for the association between the 3435C>T polymorphism and switching. In a model adjusted for age and sex, homozygous carriers of the T-T-T haplotype had an increased risk of switching ( odds ratio, 4.22; 95% confidence interval, 1.30-13.7; P = 0.017) and discontinuation ( odds ratio, 1.47; 95% confidence interval, 0.98-2.22; P = 0.063). Explained variance was 10.4% for switching and 2.5% for discontinuation. In contrast, no association was observed between the T-T-T haplotype and the prescribed dosage. In summary, this study showed that genetic variation in the ABCB1 gene might play a role in the risk of switching and discontinuation of antidepressant therapy but the clinical relevance is limited.