Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening mucocutaneous diseases. SJS/TEN mostly manifest as a reaction to new drug use, but little is known about their incidence and epidemiology. We conducted a large observational study on the epidemiology of SJS/TEN using data from the UK-based Clinical Practice Research Datalink. Among 551 validated SJS/TEN patients, we calculated an incidence rate of 5.76 SJS/TEN cases per million person-years between 1995 and 2013, which was consistent throughout the study period and was highest in patients aged 1-10 years and 80 years or older. Within a 1:4 matched case-control analysis, black and Asian patients were at a 2-fold risk of SJS/TEN when compared with white patients. Among patients with epilepsy and gout, odds ratios for SJS/TEN were significantly increased only in the presence of recent new drug treatment with antiepileptics or allopurinol, respectively. We observed statistically significant associations between SJS/TEN and pre-existing depression, lupus erythematosus, recent pneumonia, chronic kidney disease, and active cancer, but confounding by drug use needs to be followed up. This large and longitudinal observational study on the epidemiology of SJS/TEN contributes to the understanding of this still underinvestigated severe skin disease in a European and largely white study population.