Cardiac 123I-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy is used to assess the function of postganglionic presynaptic cardiac sympathetic nerve endings. 123I-MIBG cardiac uptake is markedly reduced in patients with isolated rapid eye movement (REM) sleep behavior disorder (IRBD), similar to Parkinson’s disease and dementia with Lewy bodies. As a result, it can be used as an early biomarker of IRBD. Most patients with IRBD develop synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. We aimed to investigate whether cardiac postganglionic denervation is present in patients with IRBD, as well as its possible usefulness as a marker for Lewy body disease status. This retrospective cohort study examined 306 patients (236 men and 70 women; mean age: 68.2 years; age range: 43–87 years) with polysomnography-confirmed IRBD who were followed for 1–3 months and underwent 123I-MIBG scintigraphy. We retrospectively analyzed data from 306 patients with polysomnography-confirmed IRBD, and their longitudinal outcomes were documented at two centers. Among IRBD patients, reduced 123I-MIBG uptake was observed in the early and delayed images in 84.4% and 93.4% of patients, respectively, whereas 88.6% of the patients had a high washout rate. This large Japanese two-cohort study (n = 306) found that 91 patients (29.7%) developed an overt synucleinopathy (51 Parkinson’s disease, 35 dementia with Lewy bodies, 4 multiple system atrophy, and 1 cerebellar ataxia) during a mean follow-up duration of 4.72 ± 3.94 years, with a conversion risk of 14.5% at 3 years, 25.4% at 5 years, 41.4% at 8 years, and 52.5% at 10 years. On the other hand, among patients with heart-to-mediastinum ratio < 2.2 in the delayed images (n = 286), 85 (29.7%) developed Parkinson’s disease or dementia with Lewy bodies during a mean follow-up duration of 4.71 ± 3.94 years, with a conversion risk of 14.5% at 3 years, 25.6% at 5 years, 42.0% at 8 years, and 51.0% at 10 years. Among the 33 patients who underwent repeat 123I-MIBG scintigraphy, there was a progressive decline in uptake over the next 4.2 years, with patients exhibiting reduced uptake progressing to Parkinson’s disease or dementia with Lewy bodies. In contrast, patients without decreased MIBG uptake progressed to multiple system atrophy. Reduced cardiac 123I-MIBG uptake was detected in over 90% of IRBD patients, with progression to Parkinson’s disease or dementia with Lewy bodies, rather than multiple system atrophy, over time. Reduced 123I-MIBG uptake is a robust maker for Lewy body disease among IRBD patients.