Background: We previously reported that pertuzumab (P) retreatment in combination with trastuzumab (T) + chemotherapy based on physician’s choice (C) (PTC) significantly improved investigator-assessed progression-free survival (PFS) compared with T + C (TC) in patients with HER2-positive locally advanced/metastatic breast cancer (LA/MBC) previously treated with P-containing regimens in the phase III PRECIOUS study. Here we report updated OS at the median follow-up of 27.4 mo. Methods: Patients previously treated with P-containing regimens as 1^st/2^nd-line treatment for LA/MBC were randomly assigned 1:1 to two groups, PTC group and TC group, stratified by estrogen receptor (ER) status, previous treatment duration of P, number of previous chemotherapy regimens, and presence or absence of visceral metastasis. The primary endpoint was investigator-assessed PFS. The key secondary endpoints included OS, independent reviewer assessed PFS and safety. Superiority of PTC to TC will be tested using a log-rank test and a one-sided P-value of less than 0.05 will be considered an indicator of superiority. The distribution of OS will be estimated using the Kaplan-Meier method. In addition, the hazard ratio and one-sided 95% CI of the therapeutic effect between the groups will be calculated using the Cox proportional hazard model. Results: Of the 219pts enrolled, 217 (108 PTC, 109 TC) were included in the intent-to-treat analysis. At the data cutoff (Dec 31, 2021), OS and PFS events were 138 (63.6%) and 190 (87.6%), respectively. Updated median OS was significantly longer in the PTC group (median OS 36.2 vs. 26.5 mo.; HR = 0.73 [one side 95%CI upper limit, 0.97]; log-rank test p = 0.0323). In a prespecified subgroup analysis for OS including ER, visceral metastases, number of previous chemotherapy regimen was broadly constant without disease-free interval. Updated median investigator-assessed PFS (5.5 vs. 4.2 mo.; HR = 0.81 [one side 95%CI upper limit, 1.03]; stratified log-rank test p = 0.019) were also significantly better in the PTC group. Median PFS by independent review did not show the difference between two groups (4.4 vs. 4.4 mo.; HR = 1.03 [one side 95%CI upper limit, 1.36]; log-rank test p = 0.561). The serious adverse event rate did not differ between the groups (19.0% vs. 23.1%). There were no new safety signals in the two groups. Conclusions: Retreatment of P in combination with TC demonstrated significantly improved OS compared to TC. HER2 dual blockade with PT can contribute to improve survival in patients previously treated with P-containing regimens as 1^st/2^nd-line treatment for LA/MBC. Clinical trial information: NCT02514681.