To compare contrast-enhanced spectral mammography (CESM) with mammography (Mx), ultrasound (US), and magnetic resonance imaging (MRI) regarding breast cancer detection rate and preoperative local staging. This prospective observational, single-centre study included 128 female patients (mean age 55.8 ± 11.5 years) with a newly diagnosed malignant breast tumour during routine US and Mx were prospectively enrolled. CESM and MRI examinations were performed within the study. Analysis included interreader agreement, tumour type and grade distribution, detection rates (DR), imaging morphology, contrast-enhancement and was performed by two independent readers blinded to patient history and histopathological diagnosis. Assessment of local disease extent was compared between modalities via Bland-Altman plots. One-hundred-and-ten tumours were classified as NST (85.9%), 4 as ILC (3.1%) and 10 as DCIS (7.8%). DR was highest for MRI (128/128, 100.0%), followed by US (124/128, 96.9%) and CESM (123/128, 96.1%) and lowest for conventional Mx (106/128, 82.8%) (p = 0.0002). Higher breast density did not negatively affect DR of US, CESM or MRI. Local tumour extent measurements based on CESM (Bland-Altman bias 6.6, standard deviation 30.2) showed comparable estimation results to MRI, surpassing Mx (23.4/43.7) and US (35.4/40.5). Even though detection of multifocality and multicentricity was highest for CESM and MRI (p < 0.0001), second-look rates, i.e., targeted US examinations after MRI or CESM, were significantly lower for CESM (10.2% of cases) compared to MRI (16.2%) with a significantly higher true positive rate for CESM (72.0%) vs. MRI (42.5%). CESM is a viable alternative to MRI for lesion detection and local staging in newly diagnosed malignant breast cancer and provides higher specificity in regard to second-look examinations.