Expression of the p16^INK4a tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age‐induced functional decline of certain self‐renewing compartments. These observations have suggested that p16^INK4a expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16^INK4a expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T‐lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16^INK4a, but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16^INK4a expression did not independently correlate with gender or body‐mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16^INK4a expression was associated with plasma interleukin‐6 concentration, a marker of human frailty. These data suggest that p16^INK4a expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.