Abstract BACKGROUND Multifocal glioblastoma(MF-G) are often clustered with presumed uniform worse prognosis. This study explores varying patterns of infiltration of MF-G in relation to radiological features, including presence of contiguous MRI T2-weighted abnormalities and adjacent neural tract pathway involvement. METHODS Consecutive patients with glioblastoma from 2016-2020 managed under EORTC-NCI(Stupp60Gy) Protocol had manual tumour segmentation on T1gd and T2w sequences. Multifocal disease was defined as T1gd or solid T2w-abnormality a minimum of 10mm from the dominant lesion. Number of foci, maximum dimension, cortical/white matter site and distance from dominant lesion were recorded. Presence of contiguous T2w-abnormality was recorded, and correlated to ten major neural tract pathways. Progression-free(PFS) and overall survival(OS) were analysed. RESULTS Forty of 177 patients(23%) were identified with MF-G. These had less near-total resection(p = 0.001), but no difference in ECOG(p = 0.16), or MGMT-methylation(p=0.23). Foci had median size of 14.5mm (q1-3: 10-20); 73% enhancing and 58% solitary. Median distance from dominant lesion was 23mm (q1-3:15-25). Contiguous T2w abnormality and involvement of identified neural tract was evident in 78% and 83% respectively. The multifocal lesion was based in cortex in 33%, and white matter in 67%. Survival outcomes were worse with MF-G: OS (p < 0.01) was 16.0 months (95%CI: 13.6-18.4) versus 19.9 months (95%CI: 17.6-22.2); and PFS (p = 0.01) was 10.8 months (95%CI: 9.9-11.7) versus 13.6 months (95%CI: 11.1-16.1). Improved PFS was associated with larger lesion size(p = 0.04), and cortical lesions(0.04). Those MF-G with contiguous T2w-abnormality(p = 0.06); identified neural tract(p = 0.07) or enhancement(p = 0.08) had trend to worse PFS. MGMT(p = 0.10), ECOG(p = 0.62) and extent of resection(p = 0.07) were not associated with PFS, nor radiological factors of foci number(p = 0.19) and lesion distance(p = 0.16). CONCLUSIONS Radiological pattern of infiltration in MF-G is associated with different natural history. Improved PFS was associated with cortical foci without contiguous T2 abnormality or tract involvement. Recognising infiltration patterns may impact on RT target volume delineation and understanding prognosis.