The present study was undertaken to investigate prospective change in the prevalence of coronary microvascular dysfunction (CMD) and obstructive coronary artery disease (CAD) in a cohort of subjects with systemic lupus erythematosus (SLE) initially evaluated for anginal chest pain (CP). Prior work documented a relatively high prevalence of CMD in the absence of obstructive CAD in subjects with SLE. Twenty female SLE subjects with CP who underwent stress cardiac magnetic resonance imaging (CMRI) and coronary computed tomography angiography at baseline were reevaluated at 5 years. Seventeen subjects (85%) were available and reenrolled, of which 11 (65%) had persistent CP at follow-up. Fourteen subjects had complete follow-up CMRI, of which 36% (n = 5) demonstrated CMD at follow-up. Further, 25% (1 of 4) of the originally abnormal myocardial perfusion reserve index (MPRI) findings at baseline were lower at follow-up, while 2 additional abnormal MPRI findings at follow-up were noted in previously normal MPRI results. The prevalence of CMD and nonobstructive/obstructive CAD both was unchanged between baseline and follow-up, respectively (both P values not significant). During follow-up, 33% of subjects (5 of 15) had adverse cardiac outcomes, including pericarditis, unstable angina, or intracranial aneurysm clipping procedure. At the 5-year follow-up of SLE subjects with CP who were evaluated at baseline and follow-up, a majority had persistent CP, and nearly one-half had similar or worse myocardial perfusion consistent with CMD without obstructive CAD. These findings propose an alternative explanation for CP in SLE subjects compared to the more common SLE-related accelerated obstructive CAD accounting for CP and adverse outcomes. These findings support further studies of CMD as an etiology for cardiac morbidity and mortality in SLE.