Increased arterial stiffness has emerged as a strong predictor of future cardiovascular events and all-cause mortality. The aim of this study was to elucidate influences of endothelin (ET)-related genetic polymorphisms and regular physical activity on age-related arterial stiffening through a 10-year longitudinal study. A decadal change in brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, was evaluated retrospectively among 92 volunteers (63 ± 14yrs, 51 men). The targeted single-nucleotide polymorphisms were ET-A receptor SNP rs5333 (ET-A) and ET-B receptor SNP rs5351 (ET-B). Subjects with either ET-A TC or CC genotypes exhibited significantly greater increases in baPWV (+15.3 ± 11.7 and +16.6 ± 15.7%/dec, respectively) than ET-A TT genotype holders (+9.2 ± 9.0%/dec), while subjects with the ET-B GG genotype showed a significantly greater increase in baPWV (+17.7 ± 14.1%/dec) than other ET-B genotype holders (AA: +9.5 ± 10.0%/dec; AG: +11.2 ± 9.6%/dec). The combination of these ET-related genetic risks was associated with a 2.4 times greater decadal increase in baPWV compared with no genetic risk (+8.1 ± 8.4 vs. 19.5 ± 16.0%/dec). In contrast, individuals engaging in >15 METs·hours/week of aerobic exercise showed substantially smaller increases in baPWV (+5.0 ± 9.7%/dec) compared with their physically-inactive peers (≈+13%/dec). These differences remained significant after adjusting for confounding factors, including baseline baPWV and ET-related genotype risk. Our current longitudinal study found that ET-related gene polymorphisms contribute to diverse age-related changes in arterial stiffness, and that regular sufficient aerobic exercise attenuates the age-related arterial stiffening independently of ET-related gene polymorphisms.