Background: In MA.31 the lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We previously reported the positive prognostic utility of pretreatment serum PD-L1 in 63 trastuzumab-treated patients (ASCO 2017, #1024), and here we evaluated it in the trastuzumab arm of MA.31. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positive patients; in the trastuzumab arm 186 patients had pretreatment serum available.TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Stratified step-wise forward Cox multivariate analysis was used for PFS and OS. Results: In univariate analysis for PFS, serum PD-L1 was not a significant biomarker for PFS. In univariate analysis for OS, higher serum PD-L1 was a significant biomarker for shorter OS (continuous PD-L1: HR 3.86, p = 0.044; quartiles of PD-L1: HR 1.55, p = 0.002; median cutpoint PD-L1: HR 2.16, p = 0.014). In multivariate analysis for OS [14 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, serum PD-L1], elevated serum PD-L1 was a significant independent covariate [continuous PD-L1: HR 22.7, p = 0.001; median cutpoint PD-L1: HR 2.91, p = 0.0061 (Table)]. Conclusions: In the CCTG MA.31 trial, elevated pretreatment serum PD-L1was associated with a shorter OS (but not PFS) with trastuzumab treatment. Immune evasion by the tumor may decrease the effectiveness of trastuzumab therapy. Elevated serum PD-L1 may identify patients who would benefit from addition of an immune checkpoint inhibitor.