Question Are the different definitions used to assess hyperprogressive disease during immunotherapy for non-small cell lung cancer representative of the same tumoral behavior? Findings For this multicenter cohort study of 406 patients with advanced non-small cell lung cancer treated with programmed cell death 1/programmed cell death 1 ligand inhibitors, the 5 disease definitions assessed resulted in diverse incidences, different patient characteristics, and different associations with survival outcomes. A new criterion of difference in tumor growth rate of greater than 100 showed more accuracy in assessing hyperprogressive disease. Meaning These findings suggest that the 5 definitions assessed are not representative of the same tumoral behavior.