Background Hyperkalemia is a potentially dangerous electrolyte abnormality with a reported incidence of 1-10 % in hospitals. Patients are especially at risk of developing this complication if they use a combination of potassium supplements and potassium sparing diuretics or renin-angiotensin-aldosterone- system (RAAS) inhibitors. Previous studies on the occurrence of hyperkalemia in patients who use multiple potassium influencing drugs simultaneously were either small in sample size or did not investigate the full range of drugs involved. Objective To assess the prevalence of hyperkalemia and to identify risk factors for its development in hospitalised patients using potassium supplements, potassium-sparing diuretics and/or RAAS-inhibitors concurrently. Setting The study was conducted at the Onze Lieve Vrouwe Hospital in Amsterdam, The Netherlands from January 2009 to May 2010. Method A retrospective, nested case-control study included hospitalised patients who used a combination of potassium-influencing drugs. Cases were patients with serum potassium C5.5 mmol/l, controls were patients with normal serum potassium levels. Cases and controls were included in a ratio of 1:2. The following known risk factors associated with hyperkalemia were recorded and statistically analyzed: diabetes mellitus, congestive heart failure, decreased renal function, advanced age, gender and use of heparin, digoxin, non-steroidal anti-inflammatory drugs, beta-blockers, calcineurin antagonists and trimethoprim. Main outcome measure Identify risk factors for the development of hyperkalemia as a result of the concurrent use of potassium supplements, RAAS inhibitors and/or potassium-sparing diuretics. Results Of 774 patients included in this study, 52 patients developed hyperkalemia; a prevalence of 6.7 %. The only risk factor found to be significantly associated with hyperkalemia was lowered renal function, expressed as estimated glomerular filtration rate (eGFR) \50 ml/min (adjusted OR 5.08; 95 % CI 2.46-10.48). None of the other tested risk factors was identified as significant. Conclusion This study showed that decreased renal function (eGFR\50 ml/min) was associated with a fivefold increased risk for hyperkalemia in patients using potassium-influencing drugs. While previous studies showed that hyperkalemia substantially increases below a threshold of eGFR\30 or 40 ml/min, we observed a lower threshold of eGFR \50 ml/min. It is therefore recommended that physicians should be particularly alert while monitoring the use of potassium-influencing drugs in patients with decreased renal function.