Sodium polystyrene sulfonate (SPS) is well used for hyperkalemia. A recent study has shown that SPS may bind to other drugs in the digestive tract. However, there are few reports about the effect of concomitant drug use on serum potassium level variations. Therefore, this study aimed to investigate the effect of concomitant drug use on the variation of serum potassium levels among patients taking SPS. In total, 632 patients were newly prescribed with SPS from 2017 to 2019, and 186 patients were evaluated in this study. Further, the association between increase in serum potassium levels and concomitant drug use was investigated. We classified patients into the Grade 1 (G1) group and the Grade 2–4 (G2–4) group according to baseline serum potassium level by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. There was the significant decrease in serum potassium and chloride levels and the increase in serum sodium levels after SPS treatment. In addition, therapy with SPS might improve renal function. The concomitant use of imidapril in the G1 group (odds ratio: 4.4, 95% confidence interval: 1.1–11.7, p = 0.0394) and nifedipine in the G2–4 group (odds ratio: 7.3, 95% confidence interval: 1.5–35.5, p = 0.0139) were significantly associated with the increase in serum potassium levels after SPS treatment. These associations might be affected by not only adverse drug reactions but also binding of other drugs to SPS. Hence, concomitant drug use may affect the efficacy of SPS.