Comparison of monotherapy sodium zirconium cyclosilicate (SZC) versus sodium polystyrene sulfonate (SPS) is lacking. We aimed to evaluate the effectiveness of SZC versus SPS for acute potassium lowering. This retrospective cohort study included hospitalized adult patients with acute hyperkalemia treated with SZC or SPS monotherapy. The primary outcome was time to normalization of serum potassium. Secondary outcomes included necessity of additional treatment, achievement of normokalemia at 1, 2, 4, 8, and 24 hours, and change in serum potassium from baseline to 1, 2, 4, 8, and 24 hours. Fifty-one patients received SZC and 50 received SPS. Mean baseline potassium was 5.4 mmol/L for both groups. Median time to normokalemia was 14 (IQR 8-20) hours in the SZC group versus 17 (IQR 10-21) hours in the SPS group ( P = .26). Normokalemia was achieved at 24 hours in 80% versus 77% in each group, respectively ( P = .56). Six patients per group required additional treatment ( P = .97). Mean serum potassium at all time points was numerically lower with SZC, but statistical significance was only observed at hour 8 (4.6 vs 5.0 mmol/L, P = .005), which was associated with a −0.77 versus −0.51 mmol/L decrease in serum potassium from baseline in each group, respectively ( P = .026). SZC monotherapy is at least as effective as SPS in treating mild hyperkalemia and may reduce serum potassium more quickly and to a greater degree than SPS. Future research in more severe hyperkalemia and with monitoring of potassium at regular intervals is needed to better understand the role and potential advantages of SZC over SPS.