This is a nested case-control study within a cohort of all patients who were new users of either calcium channel blockers (CCBs) or drugs interacting with the renin-angiotensin system (RAS). The sample was obtained from the Integrated Primary Care Information (IPCI) database in the Netherlands and consisted of new users of either CCBs (dihydropyridine derivatives, phenylalkylamine derivatives, and benzothiazepine derivatives) or RAS drugs (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers). The source population comprised all subjects 18 years and older who were registered with general practitioners participating in the IPCI project for at least 1 year. The study period started on January 1, 1996, and ended on September 31, 2006. From the medical records of approximately 800,000 patients, a study cohort of 20,636 persons who started with CCBs or an RAS during the study period were selected, and 103 patients were identified with definite gingival hyperplasia. To these cases, 7677 matched controls based on gender, birth date, and index rate (date of the diagnosis of gingival hyperplasia) were selected. The median age of the cases was 60.9 years (SD 15.2), and most were female (58.3%). The intake of CCBs and its association with the development of gingival hyperplasia, both in terms of the specific drugs and the dosages used. Patients developing gingival hyperplasia during follow-up. A patient was classified as having gingival hyperplasia if symptoms were present and a dentist and/or a general practitioner had confirmed the diagnosis. For each case, potential controls were selected and matched on gender, age (year of birth), and index date (date of the diagnosis of gingival hyperplasia). Exposure (intake of CCBs or RAS) and other known risk factors for gingival hyperplasia (pregnancy, diabetes, and smoking), as well as cardiovascular risk factors (hypertension, angina pectoris, congestive heart failure, hypercholesterolemia, prior myocardial infarction, transient ischemic attack, dyslipidemia, and stroke) were assessed at the time of the index date, both for cases and for controls. Exposure at the index date was categorized into 3 mutually exclusive groups, namely current, past, and no use. For current users of CCBs, the effect of daily dose and treatment duration was studied Current use of CCBs (compared with no use of CCBs regardless of RAS use) doubled the risk of gingival hyperplasia (adjusted odds ratio [OR adj] 2.2, 95% confidence interval [CI]: 1.4-3.4). No association between past use of CCBs and gingival hyperplasia was observed. The current use of nifedipine (OR adj 2.9, 95% CI: 1.6-5.5), diltiazem (OR adj 2.9, 95% CI: 1.3-6.5), dihyropyridine, and benzothiazepine derivatives was associated with an increased risk of gingival hyperplasia compared with no use of CCBs or anytime use of RAS drugs. A significant dose response was observed in current users of CCBs. This risk doubled for doses equal to 1 defined daily dose (DDD) equivalent (OR adj 2.2, 95% CI: 1.3-3.7) and tripled for daily dosages above 1 DDD (OR adj 3.0, 95% CI: 1.6-.5). Confounding by severity of hypertension and other known risk factors for gingival hyperplasia was not observed. This nested case-control study, in a cohort of patients newly treated with CCBs and/or RAS drugs, showed that current use of CCBs was associated with an increased risk of gingival hyperplasia. Copyright © 2012. Published by Mosby, Inc. All rights reserved.