Purpose The role of gray matter in Multiple sclerosis (MS) is increasingly evident; however conventional magnetic resonance (MR) images demonstrate limitations in cortical lesion (CL) identification. Perfusion imaging appears sensitive to changes in tissue type and disease severity in MS. We sought to utilize bookend perfusion to quantify parameters in healthy controls (HC), normal appearing and lesional tissue at different RRMS stages. Methods Thirty-nine RRMS patients and 19 age-matched HC were prospectively recruited. MACFIMS battery was used to assess cognitive performance. Perfusion parameters including cerebral blood flow (CBF) and volume (CBV) and mean transit time (MTT) were compared for HC, normal appearing and lesional tissue for all study groups. Dispersion of perfusion measures for white matter lesion (WML) and CLs were assessed. Results Twenty of the 39 RRMS patients were cognitively impaired (RRMS-I). Significant differences were displayed between all RRMS subgroups and HC except for normal appearing gray matter (NAGM) CBV between HC and unimpaired RRMS patients (RRMS-NI) and for all normal appearing white matter (NAWM) perfusion parameters between HC and RRMS-NI. WML but not CL perfusion was significantly reduced in RRMS-I versus RRMS-NI. Perfusion reduction with disease progression was greater in NAGM and NAWM compared to CL and WML. Smaller dispersion was observed for CLs compared to WML for each perfusion parameter. Conclusion Quantitative GM and WM analysis demonstrates significant but disproportionate WML, CL, NAWM and NAGM changes present between healthy controls and RRMS patients with and without cognitive impairment necessitating absolute rather than relative lesion perfusion measurement.