The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose–response analyses were conducted for both the entire cohort and the exposed group only. A dose–response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose–response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease.