AbstractChemotherapy‐induced thrombocytopenia (CIT) is a common complication of cancer treatment. Evidence has emerged supporting use of romiplostim to treat CIT but predicting clinical response to romiplostim is not possible. To determine utility of endogenous thrombopoietin (TPO) as a biomarker of romiplostim response, we performed an observational cohort study of patients with CIT and known baseline TPO levels receiving romiplostim. For weekly on‐romiplostim platelet (Plt) count assessment, clinical response was defined as Plt ≥ 75 × 109/L and ≥ 30 × 109/L above pretreatment baseline. Overall, moderate, and superior classes of treatment response were defined based on fraction of Plt assessments meeting clinical response criteria (> 0, ≥ 0.6, and ≥ 0.8, respectively). Sixty‐three patients with CIT were included; median age was 62 years, 41.3% were female, and median (IQR) romiplostim treatment duration was 14 (4–38) weeks. Median (IQR) TPO was lower in patients achieving moderate response to romiplostim vs those who did not, 234 (135–1085) pg/mL vs 665 (244–1970) pg/mL (p = .034) and lower still in patients achieving superior response vs those who did not, 212 (91–690) pg/mL versus 559 (173–1851) pg/mL (p = .023). Negative correlations were found between TPO level and baseline Plt and TPO level and response fraction. A positive correlation was found between TPO level and lowest effective romiplostim dose. In receiver operating characteristic (ROC) analysis, optimally discriminant TPO level thresholds (as defined by Youden's Index) were ≤ 457 pg/mL for moderate response and ≤ 260 pg/mL for superior response. In conclusion, TPO levels predict response to romiplostim in CIT, with lower levels predicting improved probability and depth of response.