Background:　Advanced　lung　adenocarcinoma　patients　often　develop　resistance　to　EGFR　tyrosine　kinase　inhibitors　(EGFR-TKIs),　leaving　uncertainties　regarding　subsequent　treatment　strategies.　Although　personalized　therapy　targeting　individual　acquired　resistances　(ARs)　shows　promise,　its　efficacy　has　not　been　systematically　compared　with　platinum-containing　doublet　chemotherapy,　a　widely　accepted　treatment　after　EGFR-TKIs　failure.　Methods:　A　retrospective　dual-center　study　was　conducted　involving　patients　with　advanced　lung　adenocarcinoma　and　EGFR　mutations　who　developed　resistance　to　EGFR-TKIs　between　January　2017　and　December　2022.　Eligible　patients　were　adults　aged　18 years　or　older　with　an　Eastern　Cooperative　Oncology　Group　score　of　0–1,　normal　organ　function,　and　no　prior　chemotherapy.　Patients　were　divided　into　the　chemotherapy　group　(CG)　or　personalized　therapy　group　(PG)　based　on　the　treatment　received　after　disease　progression.　The　primary　endpoints　were　progression-free　survival　(PFS)　and　objective　response　rate　(ORR).　Results:　Of　the　144　patients　enrolled,　there　were　53　patients　in　the　PG　and　91　patients　in　the　CG.　The　PG　acquired　resistance　to　EGFR-TKIs　through　the　MET　amplification　(27,　50%)　and　small　cell　lung　cancer　transformation　(16,　30%)　and　18%　of　them　reported　multiple　resistance　mechanisms.　The　ORR　of　the　PG　was　similar　to　that　of　the　CG　(34%　vs.　33%,　P　=　1.0)　and　the　PFS　of　the　PG　patients　was　not　statistically　different　from　that　of　their　CG　counterparts　[4.2 months　(95%　CI:　3.6–4.8 months)　vs.　5.3 months　(95%　CI:　4.6–6.0 months),　P　=　0.77].　Conclusions:　These　findings　suggest　that　the　therapeutic　efficacy　of　chemotherapy　approximates　to　that　of　personalized　therapy,　which　signifies　that　chemotherapy　is　still　a　reliable　choice　for　patients　who　develop　resistance　to　EGFR-TKIs　and　that　further　research　is　awaited　to　explore　the　benefit　of　personalized　treatment.　©　The　Author(s)　2024.