OBJECTIVE To assess the diagnostic efficacy of contrast-enhanced digital mammography (CEDM) in breast cancer detection in comparison to synthetic two-dimensional mammography (s2D MG), digital breast tomosynthesis (DBT) alone and DBT supplemented with ultrasound examination in females with dense breast with histopathology as the gold-standard. METHODS It was a prospective study, where consecutive females presenting to symptomatic breast clinic between April 2019 and June 2020 were evaluated with DBT. Females who were found to have heterogeneously dense (ACR type C) or extremely dense (ACR type D) breast composition detected on s2D MG were further evaluated with high-resolution breast ultrasound and thereafter with CEDM, but before the core biopsy or surgical excision, were included in the study. s2D MG was derived from post-processing reconstruction of DBT data set. Females with pregnancy, renal insufficiency or prior allergic reaction to iodinated contrast agent were excluded from the study. Image interpretation was done by two experienced breast radiologists and both were blinded to histological diagnosis. RESULTS This study included 166 breast lesions in130 patients with mean age of 45 ± 12 years (age range 24-72 years). There were 87 (52.4%) malignant and 79 (47.6%) benign lesions. The sensitivity of CEDM was 96.5%, significantly higher than synthetic 2D MG (75.6%, p < 0.0001), DBT alone (82.8%, p < 0.0001) and DBT + ultrasound (88.5%, p = 0.0057); specificity of CEDM was 81%, significantly higher than s2D MG (63.3%, p = 0.0002) and comparable to DBT alone (84.4%, p = 0.3586) and DBT + ultrasound (79.7%, p = 0.4135). In receiver operating characteristic curve analysis, the area under the curve was of 0.896 for CEDM, 0.841 for DBT + ultrasound, 0.769 for DBT alone and 0.729 for s2D MG. CONCLUSIONS CEDM is an accurate diagnostic technique for cancer detection in dense breast. CEDM allowed a significantly higher number of breast cancer detection than the s2D MG, DBT alone and DBT supplemented with ultrasonography in females with dense breast. CONCLUSIONS CEDM is a promising novel technology with higher sensitivity and negative predictive value for breast cancer detection in females with dense breast in comparison to DBT alone or DBT supplemented with ultrasound.