For a fixed amount of time engaged in physical activity, activity choice may affect body weight differently depending partly on other activities' displacement. Typical models used to evaluate effects of physical activity on body weight do not directly address these substitutions. An isotemporal substitution paradigm was developed as a new analytic model to study the time-substitution effects of one activity for another. In 1991-1997, the authors longitudinally examined the associations of discretionary physical activities, with varying activity displacements, with 6-year weight loss maintenance among 4,558 healthy, premenopausal US women who had previously lost >5% of their weight. Results of isotemporal substitution models indicated widely heterogeneous relations with each physical activity type (P < 0.001) depending on the displaced activities. Notably, whereas 30 minutes/day of brisk walking substituted for 30 minutes/day of jogging/running was associated with weight increase (1.57 kg, 95% confidence interval: 0.33, 2.82), brisk walking was associated with lower weight when substituted for slow walking (-1.14 kg, 95% confidence interval: -1.75, -0.53) and with even lower weight when substituted for TV watching. Similar heterogeneous relations with weight change were found for each activity type (TV watching, slow walking, brisk walking, jogging/running) when displaced by other activities across these various models. The isotemporal substitution paradigm may offer new insights for future public health recommendations.