Background: Tumor Treating Fields (TTFields) therapy is a locoregional, noninvasive modality currently approved for newly diagnosed (nd) and recurrent (r) CNS WHO grade 4 astrocytomas and glioblastoma (GBM), as well as pleural mesothelioma. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, and are generated by a portable device, delivered by skin-placed arrays. TTFields therapy is not associated with systemic toxicities, nor significant toxicities to healthy tissues or organs within the body; the most commonly associated adverse event (AE) is mild-to-moderate skin irritation beneath arrays, which can typically be managed with appropriate prophylaxis and timely intervention strategies (Lacouture et al 2014 and 2020). Here we report safety outcomes with a novel 3-day on/1-day off protocol strategy that aims to prevent and minimize skin irritation and limit treatment interruptions. Methods: In this dual center, retrospective analysis, adult patients with grade 4 ndGBM or rGBM followed a 3 days-on (72-80 h) and 1 day-off (16–24 h) TTFields therapy use schedule, with skin specific wound prevention guidance (barrier forming moisturizing topical creams and selenium-based shampoos) during the ‘off day’. Information on the presence and severity of skin AEs was collected from patient charts. Results: Adult patients (N = 76) received TTFields therapy with the 3-on/1-off protocol between 2015 and 2021 at 2 healthcare centers in the United States. Median age was 57 years (range 25–81 years) and mean time on TTFields therapy was 73 weeks. Skin AEs occurred in 5% of patients on the 3-day on/1-day off protocol, as compared to 16% and 52% reported in the randomized, phase 3 EF-11 (NCT00379470) and EF-14 (NCT00916409) studies in patients with rGBM and ndGBM, respectively. As in the clinical studies, most AEs were mild in nature. All patients who had a skin AE, prior to starting the 3-days on/1-day off protocol, received treatment to resolve the AE. In addition, no patients had to discontinue TTFields therapy or modify array placement due to skin AEs while on the 3-on/1-off protocol. Conclusions: These real-world clinical practice data confirm the positive known safety profile of TTFields therapy and are consistent with findings from clinical studies. Mild-to-moderate skin irritation is the AE most commonly associated with TTFields therapy, which is mostly manageable and resoluble. These data suggest that skin irritation could be further reduced with active preventative approaches, as described in the fractionated schema (3-days on/1-day off) protocol.