Purpose: To assess the association between all-cause mortality and hs-CRP, based mainly on the cumulative burden approach. Methods: Cohort study with adults ≥35 years from general population, using hs-CRP at two timepoints: at baseline and 30 months later to establish different exposures: change over time, cumulative, and weighted cumulative hs-CRP. The outcome was all-cause mortality assessed 7 years later. Cox models were generated to quantify the association. Results: Data from 3,119 participants (mean age 55.6 years, and 51.2% females), were analyzed. During follow-up, 164 (5.6%) deaths occurred over 20,314.5 person-years, indicating an overall mortality rate of 8.1 per 1,000 person-years. In multivariable model, hs-CRP at baseline was associated with high risk of mortality (HR = 1.77; 95%CI: 1.28–2.46). Similarly, hs-CRP change over time (HR = 2.50; 95%CI: 1.46–4.29), as well as cumulative and weighted cumulative hs-CRP (HR = 2.05; 95%CI: 1.31–3.20) were associated with greater risk of all-cause mortality. The weighted cumulative hs-CRP had the best goodness-of-fit for mortality prediction. Conclusions: In this cohort across diverse geographical low-resource settings, high levels of hs-CRP were strongly associated with all-cause mortality. Two measurements of hs-CRP are better than one to predict mortality, and the weighted cumulative approach had the best prognostic fit.