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Leisure screen time, including TV viewing, is associated with increased mortality risk. We estimated the all-cause mortality risk reductions associated with substituting leisure screen time with different discretionary physical activity types, and the change in mortality incidence associated with different substitution scenarios.A total of 423,659 UK Biobank participants, without stroke, myocardial infarction, or cancer history, were followed for 7.6 (1.4) yr, median (interquartile range [IQR]). They reported leisure screen time (TV watching and home computer use) and leisure/home activities, categorized as daily life activities (walking for pleasure, light do-it-yourself [DIY], and heavy DIY) and structured exercise (strenuous sports and other exercises). Isotemporal substitution modeling in Cox regression provided hazard ratios (95% confidence intervals) for all-cause mortality when substituting screen time (30 min·d−1) with different discretionary activity types of the same duration. Potential impact fractions estimated the proportional change in mortality incidence associated with different substitution scenarios.During 3,202,105 person-years of follow-up, 8928 participants died. Each 30-min·d−1 difference in screen time was associated with lower mortality hazard when modeling substitution of screen time by an equal amount of daily life activities (0.95, 0.94–0.97), as well as structured exercise (0.87, 0.84–0.90). Reallocations from screen time into specific activity subtypes suggested different reductions in mortality hazard: walking for pleasure (0.95, 0.92–0.98), light DIY (0.97, 0.94–1.00), heavy DIY (0.93, 0.90–0.96), strenuous sports (0.87, 0.79–0.95), and other exercises (0.88, 0.84–0.91). The lowest hazard estimates were found when modeling replacement of TV viewing. Potential impact fractions ranged from 4.3% (30-min·d−1 substitution of screen time into light DIY) to 14.9% (TV viewing into strenuous sports).Substantial public health benefits could be gained by replacing small amounts of screen time with daily life activities and structured exercise. Daily life activities may provide feasible screen time alternatives, if structured exercise is initially too ambitious.