BACKGROUND Cross-sectional plasma human immunodeficiency virus (HIV) viral load (VL) measures have proven invaluable for clinical and research purposes. However, cross-sectional VL measures fail to capture cumulative plasma HIV burden longitudinally. We evaluated the cumulative effect of exposure to HIV replication on mortality following initiation of combination antiretroviral therapy (ART). METHODS We included treatment-naive HIV-infected patients starting ART from 2000 to 2008 at 8 Center for AIDS Research Network of Integrated Clinical Systems sites. Viremia copy-years, a time-varying measure of cumulative plasma HIV exposure, were determined for each patient using the area under the VL curve. Multivariable Cox models were used to evaluate the independent association of viremia copy-years for all-cause mortality. RESULTS Among 2027 patients contributing 6579 person-years of follow-up, the median viremia copy-years was 5.3 log₁₀ copy × y/mL (interquartile range: 4.9-6.3 log₁₀ copy × y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log₁₀ copy × y/mL; 95% confidence interval [CI], 1.51-2.18 per log(10) copy × y/mL), 24-week VL (1.74 per log₁₀ copies/mL; 95% CI, 1.48-2.04 per log₁₀ copies/mL), and most recent VL (HR = 1.89 per log₁₀ copies/mL; 95% CI: 1.63-2.20 per log₁₀ copies/mL) were associated with increased mortality. When simultaneously evaluating VL measures and controlling for other covariates, viremia copy-years increased mortality risk (HR = 1.44 per log₁₀ copy × y/mL; 95% CI, 1.07-1.94 per log₁₀ copy × y/mL), whereas no cross-sectional VL measure was independently associated with mortality. CONCLUSIONS Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional VL measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of immunodeficiency.