Our aim was to develop a novel inverse optimization-based three-dimensional conformal radiotherapy (i3DCRT) technique for craniospinal irradiation. The imaging data of 20 patients with medulloblastoma were used retrospectively. The first group included 10 pediatric patients with supine position treated under anesthesia/sedation, and the second group included 10 young adult/adult patients treated with prone position. Three different treatment plans were created for each patient via i3DCRT, forward-planned three-dimensional conformal radiotherapy (f3DCRT) and intensity-modulated radiotherapy (IMRT) techniques. A total dose of 36 Gy was prescribed in 20 fractions for all plans. The comparative evaluation was conducted by using the parameters of conformity-index, homogeneity-index, and doses to the target volumes and organs at risk (OARs). The plans created with i3DCRT technique achieved better conformity and homogeneity compared to f3DCRT. In terms of OARs sparing, we found pronounced dose reductions in esophagus and heart in i3DCRT compared to f3DCRT plans. i3DCRT technique also provided a well-conformed dose distribution not superior, but comparable, to IMRT without increase in the total monitor unit per fraction (MU/fx) with respect to f3DCRT. The average monitor unit per fraction (MU/fx) for i3DCRT, f3DCRT and IMRT plans were found as 379.3, 378.0 and 1051.7 MU for the first group and 577.4, 563.5 and 1368.7 MU for the second group, respectively. Novel i3DCRT technique solves the problems associated with field junctions and beam edge matching encountered in f3DCRT plans. Additionally, i3DCRT technique can create almost similar plans as with IMRT with lower total MU/fx.