PurposeROR1 and ROR2 are Type 1 tyrosine kinase-like orphan receptors for Wnt5a that are associated with breast cancer progression. Experimental agents targeting ROR1 and ROR2 are in clinical trials. This study evaluated whether expression levels ofROR1orROR2correlated with one another or with clinical outcomes.MethodsWe interrogated the clinical significance of high-level gene expression ofROR1and/orROR2in the annotated transcriptome dataset from 989 patients with high-risk early breast cancer enrolled in one of nine completed/graduated/experimental and control arms in the neoadjuvant I-SPY2 clinical trial (NCT01042379).ResultsHighROR1or highROR2was associated with breast cancer subtypes. HighROR1was more prevalent among hormone receptor-negative and human epidermal growth factor receptor 2-negative (HR-HER2-) tumors and highROR2was less prevalent in this subtype. Although not associated with pathologic complete response, highROR1or highROR2each was associated with event-free survival (EFS) in distinct subtypes. HighROR1associated with a worse EFS in HR + HER2- patients with high post-treatment residual cancer burden (RCB-II/III) (HR 1.41, 95% CI = 1.11–1.80) but not in patients with minimal post-treatment disease (RCB-0/I) (HR 1.85, 95% CI = 0.74–4.61). HighROR2associated with an increased risk of relapse in patients with HER2 + disease and RCB-0/I (HR 3.46, 95% CI = 1.33–9.020) but not RCB-II/III (HR 1.07, 95% CI = 0.69–1.64).ConclusionHighROR1or highROR2distinctly identified subsets of breast cancer patients with adverse outcomes. Further studies are warranted to determine if highROR1or highROR2may identify high-risk populations for studies of targeted therapies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10549-023-06914-2.