Diltiazem is commonly used to treat atrial fibrillation or flutter (AFF) with rapid ventricular response (RVR). Although it is very effective for rate control, up to an 18% prevalence of reported diltiazem-induced hypotension [defined by systolic blood pressure (SBP) < 90 mm Hg], and a mean of 9.7% hypotension have been reported from several studies totaling over 450 patients. This hypotension may complicate therapy. Our objective was to determine if calcium chloride (CaCl(2)) pre-treatment would blunt a SBP drop after i.v. diltiazem, while allowing diltiazem to maintain its efficacy. A prospective, randomized, double-blind, placebo-controlled study was conducted. Seventy-eight patients with AFF and a ventricular rate of >/= 120 beats per minute were enrolled. Half received i.v. CaCl(2) pre-treatment; the other half received placebo. All patients then received i.v. diltiazem in a standard, weight-based dose. A second dose of CaCl(2) pre-treatment or placebo and diltiazem was given if clinically indicated for additional rate control. Both CaCl(2) and placebo pre-treatment groups had equal lowering of heart rate (p < 0.001). There were no adverse events in the calcium pre-treatment study arm. One patient in the placebo group became paradoxically more tachycardic and apneic after the diltiazem infusion. Although i.v. CaCl(2) seems to be equally safe compared to placebo as a pre-treatment in the management of AFF with RVR, we were unable to find a statistically significant blunting of SBP drop with CaCl(2) i.v. pre-treatment. Until further research determines a benefit exists, we cannot recommend i.v. CaCl(2) pre-treatment before diltiazem in the treatment of AFF with RVR.