Background Initially prescribed for schizophrenia and psychosis, antipsychotics are increasingly prescribed for other indications. Since the late 1990s, prescribing shifted from first-generation to second-generation antipsychotics. Aims To examine overall initiation and prevalence of antipsychotic drug prescribing in UK primary care from 1995 to 2018, stratified by gender. Method Cohort studies using UK anonymised electronic primary care data from IQVIA Medical Research Data, including over 790 general practices and registered individuals aged 18-99 years. Results Antipsychotic drug initiation was stable in the late 1990s, at 6-7/1000 person-years at risk (PYAR) in men and 9-11/1000 PYAR in women. From 2001, initiation declined, stabilising from 2005 onward at 4/1000 PYAR in men and 4-5/1000 PYAR in women. Prevalence remained consistent from 1995 to 2018: 12/1000 in men and 14/1000 in women by 2018. Initiation and prevalence were higher in women than men, but increased with age in both genders: (18-39 v. 80-99 years; incidence rate ratio (IRR) 4.85, 95% CI 4.75-4.95 in men; IRR 5.90, 95% CI 5.78-6.02 in women; prevalence rate ratio (PRR) 2.22, 95% CI 2.19-2.25 in men; PRR 4.28, 95% CI 4.24-4.33 in women). Initiation and prevalence were greater in individuals with greater socioeconomic deprivation (Townsend score of 5 v. 1; IRR 2.69, 95% CI 2.64-2.75 in men; IRR 2.19, 95% CI 2.15-2.24 in women; PRR 3.87, 95% CI 3.82-3.92 in men; PRR 2.80, 95% CI 2.77-2.83 in women). Conclusions Antipsychotic drug initiation decreased after 2001, stabilising from 2005 onward. Prevalence remained relatively consistent throughout the study period. Women had higher initiation and prevalence than men. However, both genders showed increased prescribing with age and socioeconomic deprivation.