Objective: Computed tomography (CT) is an established method for the diagnosis, staging, and treatment of multiple myeloma. Here, we investigated the potential of photon-counting detector computed tomography (PCD-CT) in terms of image quality, diagnostic confidence, and radiation dose compared with energy-integrating detector CT (EID-CT). Materials and Methods: In this prospective study, patients with known multiple myeloma underwent clinically indicated whole-body PCD-CT. The image quality of PCD-CT was assessed qualitatively by three independent radiologists for overall image quality, edge sharpness, image noise, lesion conspicuity, and diagnostic confidence using a 5-point Likert scale (5 = excellent), and quantitatively for signal homogeneity using the coefficient of variation (CV) of Hounsfield Units (HU) values and modulation transfer function (MTF) via the full width at half maximum (FWHM) in the frequency space. The results were compared with those of the current clinical standard EID-CT protocols as controls. Additionally, the radiation dose (CTDIvol) was determined. Results: We enrolled 35 patients with multiple myeloma (mean age 69.8 ± 9.1 years; 18 [51%] males). Qualitative image analysis revealed superior scores (median [interquartile range]) for PCD-CT regarding overall image quality (4.0 [4.0–5.0] vs.4.0 [3.0–4.0]), edge sharpness (4.0 [4.0–5.0] vs. 4.0 [3.0–4.0]), image noise (4.0 [4.0–4.0] vs. 3.0 [3.0–4.0]), lesion conspicuity (4.0 [4.0–5.0] vs. 4.0 [3.0–4.0]), and diagnostic confidence (4.0 [4.0–5.0] vs. 4.0 [3.0–4.0]) compared with EID-CT (P ≤ 0.004). In quantitative image analyses, PCD-CT compared with EID-CT revealed a substantially lower FWHM (2.89 vs. 25.68 cy/pixel) and a significantly more homogeneous signal (mean CV ± standard deviation [SD], 0.99 ± 0.65 vs. 1.66 ± 0.5; P < 0.001) at a significantly lower radiation dose (mean CTDIvol ± SD, 3.33 ± 0.82 vs. 7.19 ± 3.57 mGy; P < 0.001). Conclusion Whole-body PCD-CT provides significantly higher subjective and objective image quality at significantly reduced radiation doses than the current clinical standard EID-CT protocols, along with readily available multi-spectral data, facilitating the potential for further advanced post-processing.