Background: Oxaliplatin is a chemotherapeutic agent used to treat malignancies of the gastrointestinal tract. Neuropathy is a frequent dose-limiting side-effect of oxaliplatin therapy, without preventive or curative strategies. Concomitant administration of intravenous lidocaine could be a promising treatment. However, the effect of intravenous lidocaine on oxaliplatin pharmacokinetics was never studied before. We evaluated the effect of lidocaine on the area under the curve and Cmax of oxaliplatin as a part of a larger study addressing the prevention and treatment of oxaliplatin induced peripheral neuropathy with lidocaine. Methods: In this prospective cross-over trial, patients received an oxaliplatin cycle with and without lidocaine (bolus 1.5 mg kg−1 followed by 1.5 mg kg−1 h−1 in 3 h). Levels of oxaliplatin, measured as ultrafiltrable platinum were determined at 10 min after cessation of oxaliplatin infusion and hourly thereafter. Outcomes are the difference in area under the curve of oxaliplatin (primary) and the difference in the Cmax of oxaliplatin (secondary). Results: No difference in the %Δ area under the curve of oxaliplatin (–2.40 ± 7.66, 90% CI +10.50 to –15.31) was found. However, %Δ Cmax of oxaliplatin (–28.72 ± 6.01, 90% CI –18.59 to –38.85) was lower to a statistically significant extent in the chemotherapy cycle with lidocaine. No (serious) adverse events were reported. Conclusions: Lidocaine does not affect the area under the curve of oxaliplatin, which is the most important parameter in drug interaction studies and for oxaliplatin treatment effect. The lower Cmax in the chemotherapeutic cycle with lidocaine is significant and remarkable, but with an unknown exact mechanism or clinical significance, making further research desirable.