Background: The most frequent malignancy in women is breast cancer (BC). Biomarkers, like carbohydrate antigen (CA15-3) as well as carcino-embryonic antigen (CEA), remain of limited clinical value. Novel biomarkers are needed for early diagnosis. This study aimed at evaluating the role of circulating long non-coding RNA RP11-445H22.4 as a diagnostic marker of breast cancer and to assess its relation with prognostic characteristics of the disease. Methods: It was a case-control study conducted in Clinical Pathology and General Surgery Departments, Faculty of Human Medicine, Zagazig University. It involved 108 adult females: 36 females as healthy control, 36 newly diagnosed females with BC, and 36 females with benign breast lesions. Patients were diagnosed by mammography and biopsy. LncRNA RP11-445H22.4 was assessed in plasma by quantitative real-time polymerase chain reaction. Results: lncRNA RP11-445H22.4 was elevated among BC cases compared to controls as well as cases of benign breast lesions. The lncRNA RP11-445H22.4 revealed 95.9% sensitivity and 91.8% specificity for discriminating breast cancer vs. controls and benign breast lesions. CA15-3 had 77.8% sensitivity and 80.7% specificity. lncRNA RP11-445H22.4 showed 81.8% specificity versus 75.9% specificity for CA15-3 differentiating TNM stages; I and II vs. III and IV. Conclusions: LncRNA RP11-445H22.4 was up-regulated in breast cancer cases compared to controls and cases with benign breast lesions, it exhibited greater sensitivity and specificity compared to traditional biomarkers. Level of LncRNA RP11-445H22.4 was related to ER, PR and Her2/neu in BC patients. Consequently, it could serve as a potential biomarker for breast cancer diagnosis and prognosis.