Background: Gastric acid suppressing medications (AS), namely, proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RA), increase the gastric pH, which may reduce the absorption of the EGFR tyrosine kinase inhibitors (EGFR-TKIs) erlotinib and gefitinib. The aim of this study was to evaluate the clinical impact of the use of AS on the efficacy of erlotinib and gefitinib in NSCLC patients harboring EGFR mutations. Methods: From 2008 to 2011, 130 consecutive patients with advanced NSCLC harboring EGFR mutations were treated with the EGFR-TKIs erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared between patients receiving and not receiving AS. Results: Among the 130 patients treated with erlotinib or gefitinib, 47 were receiving AS (AS group), while the remaining 83 patients were not receiving AS (non-AS group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population were 60.9% and 10.0 months, respectively. In the sub-analysis carried out in the AS and non-AS groups, the ORR was 61.7% in the AS group and 60.5% in the non-AS group (p = 0.89), and the median PFS was 8.7 in the AS group and 10.7 months in the non-AS group (p = 0.13). Thus, no significant difference in the ORR or PFS was observed between the AS and non-AS groups. The median overall survival in the subject population was 31.2 months. In regard to the toxicity, the frequencies of rash (83% vs. 86%, p = 0.60) and diarrhea (34% vs. 29%, p = 0.55) were similar in the AS and non-AS groups. There were no deaths that were deemed to be treatment-related in either group. Conclusions: Concurrent use of AS did not affect the efficacy or toxicity of the EGFR-TKIs erlotinib and gefitinib in patients with NSCLC harboring EGFR mutations.