<p> Background: Data related to change in physical activity (PA) and sitting time (ST) and the association with mortality after first myocardial infarction (MI) in postmenopausal women are incomplete. A majority of the studies looking at sitting time and colorectal cancer (CRC) did not include physical activity as a potential confounder which is a significant limitation. We investigated the association between change in physical activity and sitting time among survivors of a first MI and all-cause, coronary heart disease (CHD), and cardiovascular disease mortality as well as the independent and joint associations of sitting time and physical activity with risk of incident colorectal cancer in postmenopausal women enrolled in the Women&rsquo;s Health Initiative Observational Study. </p><p> <i>Methods:</i> The WHI-OS cohort included 93,676 postmenopausal women, 50-79 years of age, enrolled between 1993 and 1998. Self-reported ST was reported at baseline, year 3 and year 6. Self-reported PA was reported at baseline and every year thereafter. All-cause, CHD and CVD mortality as well as incident colorectal cancer were the primary outcomes. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals. </p><p> <i>Results:</i> Over a 13-year follow-up, 838 had a clinical MI during follow-up and adequate data on exposures. The risk of all-cause mortality was: 0.43 (0.28-0.70) for the increased activity group and 0.54 (0.38-0.76) for the active, no change group. Women who had pre-MI levels of sitting time &lt; 8 hrs/d had an 11% increased risk (HR= 1.11, 95% CI: 1.01, 1.23) of all-cause mortality for every 1 hr/d increase in sitting time. In the CRC analysis, 74,870 participants were included. Inactivity (&le; 1.7 MET-hrs/wk) was associated with increased risk of rectal cancer and marginally significant increase in CRC (HR=2.23, 95% CI: 1.32 &ndash; 3.79) and (HR=1.20, 95% CI: 0.98 &ndash; 1.48), respectively. </p><p> <i>Conclusions:</i> In conclusion, our findings support the hypothesis that meeting the recommended physical activity guidelines pre- and post-MI has a protective role against mortality in postmenopausal women. Also increased sitting time post-MI was associated with an increased risk of all-cause mortality. Lack of PA was associated with increased risk of rectal cancer and marginally significant increase in CRC.</p>