Introduction:　Few　studies　have　investigated　the　efficacy　and　safety　of　tegoprazan-amoxicillin　(TA)　dual　therapy　for　Helicobacter　pylori　eradication.　We　aim　to　evaluate　the　effectiveness　and　safety　of　different　dosages　of　TA　dual　therapy　for　H.　pylori　eradication.　Methods:　This　prospective,　randomized,　open-label,　multicenter　study　was　conducted　at　four　centers　in　Fujian,　China.　H.　pylori-infective　patients　were　randomized　1:1:1　to　receive　one　of　the　following　treatments:　bismuth　quadruple　therapy　(BQT,　esomeprazole　20　mg　twice　daily　+　potassium　bismuth　citrate　240　mg　twice　daily　+　amoxicillin　1　g　twice　daily　+　clarithromycin　500　mg　twice　daily),　tegoprazan-amoxicillin　dual　therapies　(TA-qd,　tegoprazan　50　mg　once　daily　+　amoxicillin　1　g　thrice　daily;　TA-bid,　tegoprazan　50　mg　twice　daily　+　amoxicillin　1　g　thrice　daily)　for　14　days.　The　primary　outcome　was　noninferiority　in　eradication　rates　of　the　different　TA　groups　compared　to　the　BQT　group.　Secondary　outcomes　encompassed　an　assessment　of　adverse　reactions　and　clinical　symptom　relief.　Additionally,　exploratory　outcomes　were　focused　on　the　shifts　in　gut　microbiota　and　a　cost-effectiveness　analysis.　Results:　A　total　of　321　patients　were　enrolled.　The　eradication　rates　in　the　BQT　group,　TA-qd　group,　and　TA-bid　group　were　85.05%　(91/107),　85.98%　(92/107),　and　85.98%　(92/107)　in　the　intention-to-treat　analysis　(ITT)　(BQT　vs.　TA-qd,　95%　CI　−8.50%　to　10.36%,　noninferiority　p　=　0.012;　BQT　vs.　TA-bid,　95%　CI　−8.50%　to　10.36%,　noninferiority　p　=　0.012);　91.00%　(91/100),　91.09%　(92/101),　and　92.93%　(92/99)　in　the　modified　intention-to-treat　analysis　(mITT)　(BQT　vs.　TA-qd,　95%　CI　−7.81%　to　7.98%,　noninferiority　p　=　0.006;　BQT　vs.　TA-bid,　95%　CI　−5.62%　to　9.48%,　noninferiority　p　＜　0.001);　90.81%　(89/98),　91.00%　(91/100),　and　93.81%　(91/97)　in　the　per-protocol　analysis　(PP)　(BQT　vs.　TA-qd,　95%　CI　−7.83%　to　8.19%,　noninferiority　p　=　0.006;　BQT　vs.　TA-bid,　95%　CI　4.46%　to　10.46%,　noninferiority　p　＜　0.001).　The　incidence　of　adverse　reactions　in　the　TA-qd　and　TA-bid　groups　was　significantly　lower　than　in　the　BQT　group　(13.33%,　14.56%,　and　27.18%,　respectively;　p　=　0.017).　The　complete　remissions　of　clinical　symptoms　for　BQT,　TA-qd,　and　TA-bid　were　36.89%,　65.71%,　and　68.93%,　respectively,　had　significant　differences　(p　＜　0.001).　Two　weeks　of　TA　therapy　altered　gut　microbiota　diversity　and　composition,　but　that　recovered　4　weeks　after　discontinuation.　The　cost-effectiveness　ratios　(CERs)　for　BQT,　TA-qd,　and　TA-bid　were　1.85　CNY,　2.08　CNY,　and　3.69　CNY,　respectively.　Conclusion:　Both　TA　dual　therapies　provided　satisfactory　eradication　rates　of　＞　90%　for　eradicating　H.　pylori,　fewer　adverse　reactions,　and　greater　clinical　symptom　relief　compared　to　BQT,　with　a　mild,　reversible　impact　on　gut　microbiota.　In　addition,　the　TA　dual　therapy　with　low　doses　of　tegoprazan　showed　better　cost-effectiveness.　Trial　Registration:　Chinese　Clinical　Trial　Register　and　registration　No.:　ChiCTR2300071997.　©　2024　John　Wiley　&　Sons　Ltd.