Abstract <p>This study addresses the need for a quantitative assessment of the median lethal dose (<i>LD</i>₅₀) of caffeine in humans following oral administration. The aim was to estimate the human oral <i>LD</i>₅₀ by extrapolating data obtained from laboratory animals, including mice, rats, guinea pigs, rabbits, dogs, and cats. Extrapolation was performed using three approaches: the method of Yu.R. Rybolovlev and R.S. Rybolovlev, the guidelines of the U.S. Environmental Protection Agency (EPA), and the method of D.B. Laurence and A.L. Bacharach. The estimated human oral <i>LD</i>₅₀ of caffeine and its confidence interval are presented.</p>