Purpose Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. Patients and Methods In this randomized, cross-over, pharmacokinetic study in patients with non–small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC_0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. Results Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC_0-12h increased 39% (range, −12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC_0-12h was only slightly higher (9%; range, −10% to +30%; P = .03) after erlotinib intake with cola. Conclusion Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib.