Objective: Intravenous fluid administration is a main component of sepsis therapy, but physicians are cautious about giving fluids to end-stage renal disease (ESRD) patients out of concern for causing volume overload. We compared the outcomes of septic shock patients with and without ESRD and evaluated the association between early intravenous fluid administration and outcomes. Methods: We analyzed patients enrolled in the Protocolized Care for Early Septic Shock (PROCESS) trial, which studied different resuscitation strategies for early septic shock. Stratifying for ESRD, we compared patient characteristics, course of care, and outcomes between ESRD and non-ESRD. Using multivariable logistic regression, we determined the association between 6-hour total fluid volume (> = 30 mL/kg vs < 30 mL/kg) from preenrollment and outcomes. Results: There were 84 ESRD and 1257 non-ESRD patients. ESRD patients had a higher median Charlson Comorbidity score (5 vs 2, P < .001), higher median acute physiology and chronic health evaluation (APACHE) II score (26.5 vs 20.0, P < .001), and lower 6-hour intravenous fluid administration (54.7 vs 68.3 mL/kg, P < .001). Ninetyday mortality (33.3% vs 29.3%, P = .43) and intubation rate (31.0% vs 33.4%, P = .64) did not differ between groups. Fewer ESRD received > = 30 mL/kg (66.6% vs 86.7% P < .001). For ESRD, receipt of > = 30 mL/kg intravenous fluid did not alter any outcome. For non-ESRD patients, receiving ≥30 mL/kg of intravenous fluid was associated with increased 90-day mortality (adjusted odds ratio = 1.64; 95% confidence interval, 1.03-2.61). Conclusions: In the PROCESS trial, ESRD patients had similar outcomes to non-ESRD patients. Although ESRD patients received less intravenous fluid administration, most received over 30 mL/kg in the first 6 hours. In contrast to non-ESRD patients, receiving ≥30 mL/kg of intravenous fluid was not associated with worse outcomes in ESRD.