White matter lesions (WML) are caused by obstruction of small cerebral vessels associated with stroke risk. Craniopharyngioma (CP) patients suffer from increased cerebrovascular mortality.To investigate the effect of reduced HT volume and cranial radiotherapy (CRT) on WML in childhood onset CP patients.A cross-sectional study of 41 patients (24 women) surgically treated childhood onset CP in comparison to controls.The South Medical Region of Sweden (2.5 million inhabitants).With Magnetic Resonance Imaging (MRI) we analysed qualitative measurement of WML based on the visual rating scale of Fazekas and quantitative automated segmentation of WML lesion. Also measurement HT volume and of cardiovascular risk factors were analysed.Patients had a significant increase in WML volume (ml) (P=0.001) compared to controls. Treatment with cranial radiotherapy (CRT) vs no CRT was associated with increased WML volume (P=0.02) as well as higher Fazekas score (P=0.001). WML volume increased with years after CRT (r = 0.39; P = 0.02), even after adjustment for fat mass and age. A reduced HT volume was associated with increased WML volume (r = - 0.61, P < 0.001) and explained 26% of the variation (r2 = 0.26). Altogether 47% of the WML volume was explained by age at investigation, HT volume and CRT. Patients with more WML also had higher cardiovascular risk.CRT may be associated directly with increased WML volume or indirectly with reduced HT volume associated with higher cardiovascular risk. .Risk factors should be carefully monitored in these patients.