BACKGROUND: Fluorine-18 sodium fluoride (NaF), a bone-seeking radiopharmaceutical used to detect osseous metastases, localizes in regions of microcalcification in atherosclerosis. OBJECTIVES: To determine if atherosclerosis of penile arteries plays a role in erectile dysfunction (ED), this study analyzed NaF images in prostate cancer patients. METHODS: NaF positron emission tomography-computed tomography bone scans were evaluated in 437 prostate cancer patients (age 66.6 ± 8.7 years). Their urologic histories were reviewed for prevalent ED (diagnosed before the scan date) or incident ED (no ED at first scan, but developed during 1-year follow-up); patients with no ED (neither before the scan nor during follow-up) were included as a control group. A semicircular region of interest was set on the dorsal one-half of the penis (to avoid residual excreted activity in the urethra) on 5 contiguous slices at the base of the penis on positron emission tomography-computed tomography coronal reconstructions, and the average standardized uptake value (SUVmax) was described as NaF uptake. RESULTS: Of 437 patients, 336 (76.9%) had prevalent ED, 60 incident ED (13.7%), and 41 had no ED (9.4%). SUVmax in patients with prevalent (median 1.88; interquartile range [IQR]: 1.67 to 2.16) or incident (median 1.86; IQR: 1.72 to 2.08) ED was significantly higher than no ED (median 1.42; IQR: 1.25 to 1.54) patients (p < 0.001). After adjustment for other risk factors, the odds ratio of prevalent or incident ED was 25.2 (95% confidence interval: 9.5 to 67.0) for every 0.5-U increment in SUVmax with receptor operating characteristic area of 0.91 (95% confidence interval: 0.88 to 0.94). CONCLUSIONS: NaF uptake in penile vessels suggests that atherosclerosis is associated with ED in prostate cancer patients. The importance of NaF uptake needs to be tested in noncancer subjects and cause-effect relationship needs to be established.