Abstract Background and purpose Vascular disease is increased after radiotherapy and is an important determinant of late treatment-induced morbidity and excess mortality. This study evaluates the nature of underlying pathologic changes occurring in medium-sized muscular arteries following irradiation. Materials and methods Biopsies of irradiated medium-sized arteries and unirradiated control arteries were taken from 147 patients undergoing reconstructive surgery with a vascularised free flap following treatment for head and neck (H&N) or breast cancer (BC). Relative intimal thickening was derived from the ratio of the thickness of the intima to the thickness of the media (IMR) on histological sections. Proteoglycan, collagen and inflammatory cell content were also scored. Results Intimal thickness was significantly increased in irradiated vessels: in the H&N group the IMR was 1.5-fold greater without correction for the control artery ( p = 0.018); in the BC group the IMR increased 1.4-fold after correction for the control artery ( p = 0.056) at a mean of 4 years following irradiation. There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73% ( p = 0.024). Inflammatory cell content was increased in the intima of the irradiated H&N vessels ( p = 0.014). Conclusions Radiation-induced vascular pathology differs quantitatively and qualitatively from age-related atherosclerosis.