Background: Amplification (AMP) of PD-L1 (CD274/B7H1) has recently been linked to enhanced benefit from immune checkpoint inhibitor (ICPI) treatment. We used CGP to evaluate the PD-L1 GA landscape in cancer. Methods: Specimens from 140,411 cancers representing > 450 individual disease ontologies were sequenced using a hybrid capture-based, next-generation sequencing assay. PD-L1 protein expression was measured by immunohistochemistry (IHC) in a subset of cases using the Dako 22C3 anti-PD-L1 antibody. Results: 1383 (0.9%) tumors had PD-L1 GA (1414 GA): 879 (62%) AMP, 471 (33%) short variants (SV) and 60 (0.4%) truncating rearrangements (RE). PD-L2 (PDCD1LG2) and JAK2 were co-amplified in 94% and 82% of PD-L1 AMP samples; other genes commonly altered with PD-L1 AMP included TP53 (77%), CDKN2A/B (28%/20%), MYC (21%), and TERT (13%). For samples with RE or SV, PIK3CA (19%; 21%) GA were common and TERT GA were in 7% or 14% of samples. Most SV GA were missense (88%), compared with truncating (10%) or splice site (2%) GA. Recurrent somatic variants of unknown significance (VUS) were observed, including frameshift and missense GA that may regulate PD-L1 stability. Of 10 common tumors, breast (213) and lung (210) carcinomas (CA) represented the most PD-L1 AMP cases. Select cancers with notable PD-L1 AMP frequencies were anaplastic thyroid CA (4%), head and neck squamous CA (HNSCC) (2.5%), cervical SCC (2.6%), and breast (1.4%), lung (0.7%) and bladder (0.6%) CA. Of common tumor types, such as colorectal, pancreatic, ovarian, or prostatic CA, melanoma and glioblastoma, ≤0.3% had PD-L1 AMP. There was strong correlation between PD-L1 AMP and PD-L1 expression by IHC in NSCLC, with 89% AMP positive samples showing > 50% IHC staining and 11% with positive but < 50% staining. Major clinical responses to ICPI therapies for tumors with PD-L1 AMP will be presented. Conclusions:PD-L1 AMP or other GA occur rarely across many cancer types. Many somatic PD-L1 GA are uncharacterized VUS. PD-L1 AMP correlates with high membrane expression of PD-L1 measured by IHC and is linked to durable response to ICPI therapies. Further evaluation of PD-L1 AMP as a potential biomarker for immunotherapy selection appears warranted.