Purpose: This study aimed to explore the use of a protocol for sleep deprivation, combined with a surface optical monitoring system (OSMS)-guided radiation therapy (RT) to eliminate the need for pharmaceutical sedation of pediatric patients with cancer. Methods and Materials: The study subjects were 28 children aged 0 to 3 years undergoing intensity modulated RT. Parents used the WASPE method to keep the children awake from 6:00 am to 2:00 pm on each day of RT. To compare the potential effects of sleep deprivation versus sedation on treatment, the first 16 patients tested were alternately sleep deprived 1 day and given sedatives the next day for the duration of the RT. In all cases, RT was delivered under the real-time guidance of an OSMS. Results: Twenty-seven of 28 children successfully completed 343 fractions of OSMS-guided RT. The 5-mm threshold for intrafractional motion was exceeded, and treatment was interrupted for patient repositioning during 13 sessions (sleep deprivation: 10 of 253 fractions; sedation: 3 of 90 fractions). Among the first 16 patients, no significant differences in inter- or intrafractional errors were noted on cone beam computed tomography scanning, except for an intrafractional error in the vertical direction for the 8th patient (P =.046). No significant difference in intrafractional errors measured by OSMS was found between the sleep-deprivation and sedation groups, except for 1 in the lateral direction for the 4th patient (P =.042) and 1 in the vertical direction for the 7th patient (P =.05). No differences were found in complete blood counts between the sleep-deprivation and sedation groups. In all, 36 of 52 parents surveyed (69%) preferred sleep deprivation, and only 3 parents (6%) preferred sedatives. Conclusions: The use of a sleep-deprivation protocol with OSMS guidance allows for accurate delivery of RT to children aged 0 to 3 years without the need for sedation and without jeopardizing target coverage. This approach may be useful for children who are resistant to or cannot tolerate sedatives.