Depression is a commonly cited adverse effect of β-blockers but the evidence for a causal relationship is limited.; We aimed to explore whether β-blockers are associated with an increased risk of new-onset depression.; We conducted a case-control study using the UK population-based Clinical Practice Research Datalink (CPRD) GOLD. We identified patients aged 18-80 years with an incident depression diagnosis between 2000 and 2016, and matched controls, and estimated the risk (odds ratio [OR]) of depression in association with use of β-blockers. We also conducted analyses of exposure, categorised by number and timing of prescriptions and by indication for β-blocker use.; The study encompassed 118,705 patients with incident depression and the same number of matched controls. The odds of developing depression were increased for current short-term use of any β-blocker (adjusted OR [aOR] 1.91, 95% confidence interval [CI] 1.72-2.12), whereas current long-term use was not associated with the risk of depression compared with never use. The elevated risk of depression among short-term users was mostly confined to propranolol users with a neuropsychiatric disorder (aOR 6.33, 95% CI 5.16-7.76), while propranolol users with a cardiovascular indication were only at marginally increased risk of depression (aOR 1.44, 95% CI 1.14-1.82).; This study suggests that the association between use of β-blockers and depression may not be causal but rather a result of protopathic bias. Propranolol is often prescribed to treat neuropsychiatric symptoms, suggesting that the onset of depression may be related to the underlying indication rather than to an effect of a β-blocker therapy.