Background: Epidermal growth factor receptor (EGFR) exon 19 deletion (Ex19del) in non-small cell lung cancer (NSCLC) consists of many subtypes, and their sensitivity to tyrosine kinase inhibitors (TKIs) has not been clearly defined. This study aimed to investigate the clinical outcomes of advanced NSCLC patients with different EGFR ex19del subtypes treated with different TKIs. Methods: We retrospectively analyzed stage IIIB-IV NSCLC patients with EGFR Ex19del and first-line TKIs therapy. E746_A750del was defined as classic group, and the others as non-classic group, which was further divided into subgroups according to deletion with or without insertion, starting codon or length of deletion. The primary endpoint was progression free survival (PFS). Results: There were 17 Ex19del subtypes identified in 101 patients. The frequency of E746_A750del was 64.4% (65/101), and the top three frequent non-classic subtypes were L747_T751del (6.9%, 7/101), L747_P753delinsS (5.9%, 6/101) and E746_S752delinsV (5.0%, 5/101). In all patients, the median PFS (mPFS) of first-line TKIs in classic and non-classic groups were 14.3 months (m) and 19.3 m (p> 0.05). In non-classic group, the mPFS in deletion with insertion (delins) and without insertion subgroups were 25.3 m and 11.2 m; in deletion starting with E746 and with other codon subgroups were 29.7 m and 19.3 m; and in deletion length of 15 nucleotides (n) and of other length subgroups were 11.2 m and 25.3 m. The mPFS of these non-classic subgroups were not statistically different with that of classic group (p> 0.05). In all patients, the mPFS of first-line therapy with the 1st, 2nd and 3rd generation TKIs were 17.4 m, 15.6 m and 20.5 m, respectively (p＞0.05); in classic group, the mPFS were 14.3 m, 16.9 m and 20.5 m, respectively (p＞0.05). However, in non-classic delins subgroup (29.7 m, 15.6 m and 11.9 m) and in deletion length of ≥18 n subgroup (25.3 m，12.3 m and 11.9 m), the 1st generation TKIs had an insignificantly longest mPFS (p＞0.05). When resistant to 1st or 2nd generation TKIs, patients in classic group showed a trend of higher incidence of T790M mutation than non-classic group (72.0% vs 43.8%, p = 0.070). In multivariant analysis, pleural metastasis (PM) had interaction with Ex19del grouping, warranting stratification analysis. In patients without PM, the mPFS of first-line TKIs in classic group was significantly shorter than non-classic group (13.8 m and 29.7 m, p = 0.026). However, in patients with PM, the mPFS of classic group was numerically longer than non-classic group (16.9 m and 11.7 m, p> 0.05), with the shortest mPFS in non-classic without insertion subgroup, and in non-classic with 15 n deletion subgroup. Conclusions: In advanced NSCLC patients with EGFR Ex19del, the efficacy of first-line TKIs therapy was affected by the presence of pleural metastasis, Ex19del subtypes and different generation of TKIs.