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Introduction: There is a paucity of predictive biomarkers of efficacy for tyrosine kinase inhibitors (TKIs), which are cornerstone therapies for solid tumors. Previous studies identified a positive association between treatment-emergent macrocytosis and both progression-free survival (PFS) and overall survival (OS) in sunitinib-treated patients. We aimed to investigate similar associations in additional TKIs used for the treatment of solid tumors. Methods: This was a single-institution retrospective study that included patients if they were ≥18 years with solid tumor diagnoses (e.g., gastrointestinal stromal tumor, hepatocellular carcinoma, renal cell carcinoma [RCC], and thyroid cancer), and who were treated with axitinib, cabozantinib, imatinib, pazopanib, sorafenib, or sunitinib between 1/1/2010 and 8/15/2017. Patients were excluded if they lacked a baseline and at least one on-treatment mean corpuscular volume (MCV) measurement, or if treatment was in the neoadjuvant/adjuvant setting. Univariate survival analyses were performed using a log-rank test, while Cox Proportional Hazards were used for multivariable survival analyses. Results: In multivariable analyses of the entire study cohort (n=209), which accounted for the effects of solid tumor diagnosis and TKI selection, on-treatment MCV ≥100 fL and ΔMCV ≥10 fL from baseline were significantly associated with increased OS (P=0.013 and P=0.038, respectively) and PFS (P=0.005 and P=0.011, respectively). In multivariable analyses of the RCC subgroup (n=107), on-treatment MCV ≥100 fL and ΔMCV ≥10 fL from baseline were significantly associated with increased OS (P=0.034 and P=0.038, respectively) and PFS (P=0.0001 and P=0.026). In multivariable analyses of pazopanib-treated patients (n=80), only on-treatment MCV ≥100 fL was associated with increased PFS (P=0.018). Conclusions: Treatment-emergent macrocytosis predicts TKI treatment efficacy in solid tumors, particularly in RCC and pazopanib-treated patients. These study results provide compelling rationale to pursue future lines of prospective research inquiry clinically to validate these data, and translationally to better understand the molecular mechanisms underlying associations between treatment-emergent macrocytosis and survival.