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Background: It is unknown whether the standardized intravenous aminophylline administration following regadenoson-stress can prevent the gastrointestinal and other adverse effects associated with regadenoson., Methods: In a randomized, double-blinded, placebo-controlled clinical trial we compared the frequency and severity of regadenoson adverse effects in those who received 75 mg of intravenous aminophylline versus a matching placebo administered 2 minutes after regadenoson or 90 seconds post-radioisotope injection., Results: 248 patients [44.8% women, mean age 62.2 (± 13.3) years] were randomized to receive aminophylline (124) or placebo (124). In the aminophylline arm, there was 50% reduction in the incidence of the primary endpoint of diarrhea and abdominal discomfort [11 (8.9%) vs 22 (17.7%), P = .04] and 70% reduction in the incidence of diarrhea [4 (3.2%) vs 13 (10.5%), P = .02]. Additionally, aminophylline use was associated with 34% reduction in the secondary endpoint of any regadenoson adverse effects [55 (44.4%) vs 83 (66.9%), P < .001] and 71% reduction in headache [9 (7.3%) vs 31 (25%), P < .001]. The stress protocol was better tolerated in the aminophylline group (P = .007). The quantitative summed difference score was similar in both study groups (P = .92). There were no excess adverse events in the aminophylline arm., Conclusions: This trial supports the routine administration of IV-aminophylline to reduce the frequency and severity of adverse effects associated with regadenoson-stress.