Background. White matter lesions (WMLs) may contribute to cognitive deficits in patients with mild cognitive impairment (MCI), but their pathogenesis is complex. Fluctuations of blood pressure (BP) over 24 hours and genetic predisposition to develop vascular damage have been implicated. Methods. In 63 MCI patients 65 years old or older, BP was measured both clinically and with ambulatory BP monitoring. Patients were classified in two groups: no/very mild (n = 34) and mild to severe (n = 29) WMLs, based on a visual scale on magnetic resonance (mean age 71.8 +/- 4.7 vs 74.6 +/- 5.1, and female gender 53% vs 66%, respectively). The volume of WMLs was measured by a semi-automatic method, separately for periventricular caps and rim, periventricular confluent, subcortical punctate, and subcortical confluent. Polymorphisms of cystatin C (CST3) and cholesterol 24-hydroxylase (CYP46) genes, putative risk factors for cerebrovascular disease, were determined. Results. The prevalence of cerebrovascular risk factors was similar in the two MCI groups of different WML severity, as well as clinic and ambulatory BP. In patients with mild to severe, but not in those with no/very mild WMLs, the volume of periventricular confluent WMLs increased with increasing daytime systolic BP (regression coefficient.47, 95% confidence interval [CI],.13 to.71 vs.02, 95% CI, -.32 to.36, p =.003 for the difference between slopes). The volume of other WML subtypes was not associated with ambulatory BP. Participants carrying both CST3*B and CYP46*T alleles were overrepresented in the MCI group with mild to severe WMLs (43% vs 17%, p.03). Conclusions. BP and gene putative risk factors for cerebrovascular disease are differentially associated with WMLs in two MCI groups of different WML severity. WMLs might develop for the convergence of innate with acquired factors.