BackgroundStudies report an increased risk of self-harm or suicide in people prescribed mirtazapine compared with other antidepressants.ObjectivesTo compare the risk of serious self-harm in people prescribed mirtazapine versus other antidepressants as second-line treatments.Design and settingCohort study using anonymised English primary care electronic health records, hospital admission data and mortality data with study window 1 January 2005 to 30 November 2018.Participants24 516 people diagnosed with depression, aged 18–99 years, initially prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine, a different SSRI, amitriptyline or venlafaxine.Main outcome measuresHospitalisation or death due to deliberate self-harm. Age–sex standardised rates were calculated and survival analyses were performed using inverse probability of treatment weighting to account for baseline covariates.ResultsStandardised rates of serious self-harm ranged from 3.8/1000 person-years (amitriptyline) to 14.1/1000 person-years (mirtazapine). After weighting, the risk of serious self-harm did not differ significantly between the mirtazapine group and the SSRI or venlafaxine groups (HRs (95% CI) 1.18 (0.84 to 1.65) and 0.85 (0.51 to 1.41) respectively). The risk was significantly higher in the mirtazapine than the amitriptyline group (3.04 (1.36 to 6.79)) but was attenuated after adjusting for dose.ConclusionsThere was no evidence for a difference in risk between mirtazapine and SSRIs or venlafaxine after accounting for baseline characteristics. The higher risk in the mirtazapine versus the amitriptyline group might reflect residual confounding if amitriptyline is avoided in people considered at risk of self-harm.Clinical implicationsAddressing baseline risk factors and careful monitoring might improve outcomes for people at risk of serious self-harm.