Interventional trials indicate adverse outcomes when hemoglobin >13 g/dL is targeted in patients with chronic kidney disease (CKD) who receive erythropoiesis-stimulating agents (ESAs). It is not clear whether high-achieved hemoglobin with minimal to no ESA administration as observed in some patients with polycystic kidney disease (PKD) is also associated with poor outcomes. Survival models were examined to assess the association between hemoglobin increments and mortality in a 6-year cohort of 2,402 PKD and 110,875 non-PKD hemodialysis patients across infrequent versus frequent ESA therapy defined as ESA < 25% of cohort time versus otherwise, respectively. Mortality risk was estimated by Cox proportional regression [hazard ratio (HR) and 95% of confidence interval] analysis. Patients with PKD were aged 58 ± 13 years and included 46% women 14% Blacks, respectively. Fully adjusted death HRs of time-averaged hemoglobin increments <11.0, 12.0 to <13.0 g/dL (reference: 11.0 to <12.0 g/dL) for frequent ESA therapy were 2.57 (1.48-4.48), 0.60 (0.43-0.82), and 0.81 (0.50-1.29), whereas for infrequent ESA therapy they were 1.33 (0.47-3.78), 0.28 (0.13-0.61), and 0.22 (0.09-0.57), respectively. Hence, in patients with PKD who require infrequent ESA, incrementally higher achieved hemoglobin including > 13.0 g/dL exhibits better survival; this incremental survival gain of higher hemoglobin is not observed in patients with PKD receiving frequent ESA administration, in whom hemoglobin concentration > 13 exhibits increased mortality.