There is insufficient evidence on the utility of potassium-binding resins in patients with end-stage renal disease on dialysis. In addition, their poor tolerability raises concerns of patient adherence. We aimed to assess the efficacy of calcium resonium and investigate the impact of counseling on adherence pattern as well as treatment response. Adult patients on hemodialysis receiving calcium resonium were enrolled with a control group not on treatment. Adherence patterns and adverse effects were recorded following patient interviews. Patients were stratified into 28 adherent (A), 42 non-adherent (NA), and 30 controls (C). Patient education was undertaken, and serum potassium levels were evaluated for 3 months pre- and post-counseling with inter- and intra-group comparison. A statistically significant difference was observed between potassium levels at baseline in A and NA groups but not post-education, which was related to worsening control in former and not due to improvement in NA patients. The poor effectiveness of calcium resonium in the control of hyperkalemia was likely related to non-compliance due to gastrointestinal (GI) intolerability. Dietary indiscretions as well as lack of consistent use of cathartics may have also contributed. No difference in dialysis adequacy was noted among groups, although the contribution of residual renal function was not assessed. These findings raise concern regarding cost-efficacy of this medication and lend credence to investing in traditional measures in hyperkalemia management, namely dietary compliance and adequate dialysis. Further long-term trials are awaited to better define the role of calcium resonium in the dialysis setting.