Background: PK and PD studies demonstrate drug exposure and target saturation of immune checkpoint inhibitors (ICI) at doses below MTD. MTD remains a primary endpoint in ICI phase 1 trials and the optimal dosing to minimize toxicity and optimize response remains unclear. Methods: We analyzed clinical data from pts treated in phase 1 ICI dose escalation trials at MD Anderson Center for Targeted Therapy. Patients were stratified into a low-dose [LDG] ( < 33% MTD), medium dose [MDG] (34-66% MTD), high dose [HDG] (67-100% MTD), or very high dose [VHDG] ( > 100% MTD) group. Groups were compared for irAE, PFS, OS, ORR (CR + PR), and DCR (CR + PR + SD > 6 months). Results: Among 90 pts treated with escalating doses of ICI (57 CTLA4- and 33 PD1-based) between April 2013 and December 2015, median age was 59 years (range: 20-86 years) and 37 (41%) were females. The most common tumor types treated included renal cell carcinoma (n = 23; 25%), melanoma (n = 16; 18%), sarcoma (n = 10; 11%), and GIST (n = 10; 11%). PFS in the LDG (n = 16) was 2.76 months (mo) (95% CI 1.48-NA), MDG (n = 21) was 2.76 mo (95% CI 1.48-NA), HDG (n = 36) was 2.46 mo (95% CI 1.84-3.29), and VHDG (n = 17) was 3.68 mo (95% CI 2.76-NA). Log rank p = 0.22. OS in LDG was 6.18 mo (95% CI 3.45-NA), MDG was 17.05 mo (95% CI 3.94-NA), HDG was 5.16 mo (95% CI 4.24-7.62), and VHDG was 7.49 mo (95% CI 5.59-NA). Log rank p = 0.0070. In all evaluable patients, ORR in LDG, MDG, HDG, and VHDG was 0%, 6%, 6%, and 12% (p = 0.47) and DCR was 62%, 71%, 41%, and 81% (p = .027), respectively. irAE rates in LDG, MDG, HDG, and VHDG were 6%, 10%, 17%, and 29% (p = .045). Conclusions: Despite a dose-dependent increase in irAE, we identify no improvement in PFS, OS, or DCR with escalating doses of ICI administered in phase I trials but do detect an improvement in ORR. Prospective dose-/exposure-response relationships and biomarker-driven RP2D are warranted on all ICI dose-escalation phase 1 trials. Lower doses may reduce toxicity and cost without compromising disease control or survival.