Background: Immune checkpoint inhibitors (ICIs) are now standard therapy for adults with a range of advanced cancers, though patients receiving ICIs have knowledge deficits regarding their risks and benefits. We designed a novel educational video and question prompt list (QPL) intervention, UPLIFT, for adults initiating ICIs. In this trial, we aimed to assess the feasibility and acceptability of UPLIFT and explore its preliminary effects on immunotherapy knowledge and anxiety. Methods: We randomized 130 adult patients (age ≥ 18 years) who were initiating an ICI for advanced (stage IV or unresectable stage III) cancer to receive an educational video and QPL, which suggests questions they may ask their clinician about the goal and likelihood of benefit of ICIs. Participants received UPLIFT either prior to the start of treatment (intervention group) or after 6 weeks (waitlist control) and were randomized 1:1 using random permuted blocks with stratification by cancer type. All participants were invited to complete surveys at enrollment (baseline) and within 72 hours after their oncology appointment on the day of ICI initiation (72h). The primary outcome was feasibility, defined as 70% of approached patients enrolling in the trial and 80% of intervention participants watching the video and reviewing the QPL. We also collected patient-reported acceptability of UPLIFT (3-item survey) in the intervention group at 72h and asked patients whether they had used the QPL in their oncology visit to ask questions. Results: Of 178 eligible patients approached, 130 patients enrolled in the trial (73%) and were randomized to receive UPLIFT (n = 66) or waitlist control (n = 64); one patient in the control group withdrew consent and was not included in analysis (total n = 129). The sample included patients with melanoma (40%), lung cancer (26%), renal cell carcinoma (8%), hepatocellular carcinoma (8%) and other cancers (18%); mean age was 67. In the intervention group, 100% of patients watched the video and received the QPL; 46% reported using the QPL to ask their oncology team questions. In the acceptability survey, 94% of patients reported that they felt comfortable with the video and QPL, 89% found the video and QPL helpful in improving their understanding about medical choices, and 73% would “definitely recommend” the video and QPL to others. Preliminary effects of UPLIFT on immunotherapy knowledge and anxiety will be reported separately. Conclusions: A novel intervention to educate patients with advanced cancer about the risks and benefits of ICIs was feasible to deliver, acceptable, and helpful to patients. Given that information is one of the greatest unmet supportive care needs among patients with advanced cancer, these results demonstrate that UPLIFT may provide useful support to patients initiating ICI therapy. Clinical trial information: NCT04670445.