4π non-coplanar radiotherapy significantly improves dosimetry, but its clinical implementation on the widely available C-arm gantry system is limited by the restricted non-colliding beam angles and the complex coordination of gantry and couch motion. Alternatively, a robotic arm platform is more favorable for the non-coplanar and non-isocentric treatment, but the conflict between field size and modulation resolution needs to be managed. This study investigates the dosimetry and delivery efficiency by creating many isocenters to achieve simultaneously large field-of-view (FOV) and high modulation resolution for robotic radiotherapy. The many-isocenter optimization framework includes a least-square dose fidelity objective, a total variation term for regularizing the fluence smoothness, and a group sparsity term for simultaneous beam orientation optimization (BOO) and isocenter selection. A minimal number of candidates isocenters were identified before the optimization for efficient target coverage. The proposed algorithm was evaluated on the intensity-modulated radiotherapy (IMRT) treatment plans of 10 Head and Neck (H&N) cancer patients. Colliding beams excluded, high-resolution small-field non-isocentric 4π IMRT plans with 50cm source-to-isocenter distance (SID-50) were compared with low-resolution large-field isocentric plans with 100cm SID (SID-100). The table reports the planning target volume (PTV) and organs at risk (OARs) statistics, and the corresponding Wilcoxon signed-rank test, showing significant difference (p<0.05) in PTV homogeneity, PTV Dmax, R50, Integral dose, and OAR Dmean and Dmax. With better target coverage, SID-50 substantially improved dose conformality and reduced OAR dose. R50 and integral dose were reduced by 5.3% and 9.6% respectively. The average reduction of [Dmean, Dmax] of SID-50 from SID-100 were [2.09 Gy, 1.19 Gy] for OAR overall, [3.05 Gy, 0.04 Gy] for parotid gland, [3.62 Gy, 5.19 Gy] for larynx, and [3.27 Gy, 1.10 Gy] for mandible. The estimated delivery time of 20-beam [SID-50, SID-100] plans were [19, 18] minutes and [14, 9] minutes, assuming 5 fractions and 30 fractions, respectively. With clinically acceptable delivery efficiency, the proposed non-coplanar many-isocenter optimization is dosimetrically favorable for treating large targets with high modulation resolution.Tabled 1Abstract 2832; Table 2832Wilcoxon signed rank test of PTV and OAR statistics of SID-100 (isocentric) and SID-50 (non-isocentric) for all 10 patients.Statisticsp-valueSigned rankNumber of samplesSID-100SID-50MeanSTDMeanSTDPTV Homogeneity0.00385290.9010.0450.9060.045PTV Dmin0.749202290.9740.0190.9750.016PTV Dmax<.001380291.1270.0621.1180.061R500.00653102.3810.2362.2540.256Integral Dose0.0025510139.37738.481126.0236.139OAR Dmean0.002551017.8223.72715.7293.273OAR Dmax0.002551034.5156.31733.3256.173 Open table in a new tab