Regadenoson is a selective adenosine A2A-receptor agonist, used as a pharmacological stress agent for myocardial perfusion imaging. It is associated with frequent adverse effects (AEs), particularly among individuals younger than 65 years of age and women. Intravenous aminophylline administration following regadenoson, as described in the ASSUAGE trial, reduces the incidence of AE. In this substudy of the ASSUAGE trial, we compared the absolute and relative benefits of aminophylline administration versus placebo, between subgroups of age (<65 vs. ≥65 years) and gender (women vs. men). Study endpoints were headache, gastrointestinal AE, any regadenoson AE, and tolerability (feeling comfortable during regadenoson stress). Among patients <65years, compared with ≥65 years, aminophylline administration was associated with greater absolute risk reduction (ARR) in gastrointestinal AE (16% vs. 5%, P = 0.01) and any regadenoson AE (31% vs. 12%, P = 0.001), and with a greater absolute improvement in tolerability (21% vs. 1%, P < 0.001). Men received greater ARR in gastrointestinal AE than women (18% vs. 2%, P < 0.001). There was no difference in the ARR in other AE between subgroups. Across all subgroups, aminophylline use was associated with a consistent trend toward relative reduction in AE rates and improved tolerability. No significant interaction was identified between subgroups and aminophylline administration in reducing AE. In conclusion, although aminophylline use was associated with greater ARR in AE in certain subgroups, a consistent benefit with aminophylline administration was attained in all subgroups. Thus, to predictably reduce regadenoson AE and improve tolerability, aminophylline should be administered routinely to all patients as per the ASSUAGE protocol.