Background: Physical activity (PA) fragmentation, an emerging concept of PA patterns, indicates the frequency of transitioning from an active to a sedentary state. Whether PA fragmentation provides prognostic information beyond conventional PA measures is unclear, especially in Hispanics/Latinos. Aim: To examine the association between PA fragmentation and mortality in Hispanics/Latinos. Methods: We included 9,856 participants (mean age 41.7 [SE 0.27] years; 52.1% women) from HCHS/SOL with baseline PA evaluation from an Actical accelerometer (≥3 days with ≥10 hr/day of wear). We defined sedentary as <10 counts/min and active as ≥10 counts/min. PA fragmentation was calculated using the active-to-sedentary transition probability (ASTP), defined as the reciprocal of the average active bout duration on a minute-level basis across valid days. We used daily mean total log activity counts (TLAC) as a measure of total PA volume. We modeled the residuals of ASTP regressed on TLAC (total-PA-adjusted ASTP) to investigate ASTP independently of total PA. Deaths were identified from annual follow-up contacts until December 31, 2018. We explored multivariable Cox regression models accounting for the multi-stage sampling design. Results: There were 242 deaths (2.5%) over a mean of 7.1 years. ASTP was associated with mortality in all models ( Table ). Each 0.10-unit increase of ASTP at baseline was associated with a 38% higher mortality risk after accounting for demographic, clinical, and lifestyle factors. Similarly, the highest ASTP tertile indicated a 2-times greater risk of death compared to the lowest tertile. The results were largely similar when we modeled using total-PA-adjusted ASTP. Higher TLAC was also associated with reduced mortality. Similar results were observed after excluding early deaths (first 2 years). Conclusion: PA fragmentation was robustly associated with mortality, independent of total PA volume. Our findings support PA fragmentation as an emerging novel measure that is informative beyond total PA.