Thrombotic thrombocytopenic purpura (TTP) is a diagnostic and therapeutic emergency. Therapeutic plasma exchange (TPE) combined with immunosuppression has been the cornerstone of the initial management. To produce optimal benefits, emerging treatments must be used against a background of best standard of care. Clarifying current uncertainties is therefore crucial. The objective of this study was to analyze a large high-quality database (Marketscan) of TTP patients managed between 2005 and 2014, in the pre-caplacizumab era, in order to assess the impact of time to first TPE and use of first-line rituximab on mortality, and whether mortality declines over time. Among the 1096 included patients (median age 46 IQR 35-55, 70% female), 28.8% received TPE before day 2 in the ICU. Hospital mortality was 7.6% (83 deaths). Mortality was independently associated with older age (hazard ratio HR, 1.024/year; 95% confidence interval 95%CI, 1.009-1.040), diagnosis of sepsis (HR, 2.360; 95%CI 1.552-3.588), and the need for mechanical ventilation (HR, 4.103; 95%CI, 2.749-6.126). Factors independently associated with lower mortality were TPE at ICU admission (HR, 0.284; 95%CI, 0.112-0.717), TPE within one day after ICU admission (HR, 0.449; 95%CI, 0.275-0.907), and early rituximab therapy (HR, 0.229; 95% CI, 0.111-0.471). Delayed TPE was associated with significantly higher costs. Immediate TPE and early rituximab are associated with improved survival in TTP patients. Improved treatments have led to a decline in mortality over time, and alternate outcome variables such as the use of hospital resources or longer term outcomes therefore need to be considered.