Background and Objective: Pazopanib is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and soft-tissue sarcoma. At the approved dose of 800 mg once daily (QD), 16–20% of patients are being underdosed and at risk of decreased efficacy. This study aimed to show whether splitting intake moments, as a cost-neutral alternative to a dose increase, leads to an increased exposure. Methods: We performed a cross-over trial comparing the pharmacokinetics of pazopanib 800 mg QD with pazopanib 400 mg twice daily. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Results: Nine evaluable patients were included. At the 800 mg QD dosing schedule, median minimum plasma concentration (Cmin), area under the concentration–time curve from 0 to 24 h (AUC0–24h), and maximum plasma concentration (Cmax) were 23.2 mg/L (interquartile range 18.5–27.6), 773 mg h/L (557–1009), and 40.6 mg/L (36.4–56.4) compared with 41.6 mg/L (30.5–55.8, p = 0.004), 942 mg h/L (885–1419, p = 0.027), and 50.2 mg/L (46.8–72.5, p = 0.074) at 400 mg twice daily. One patient experienced a grade 3 event (i.e., diarrhea). Conclusions: This study demonstrates that splitting intake moments of pazopanib leads to a 79% increase in Cmin, with acceptable tolerability. Therefore, this new dosing schedule offers a cost-neutral opportunity to optimize treatment in patients with low exposure. Clinical Trial Registration: NL6137 (http://www.trialregister.nl).