Objective: To differentiate between reactive plasmacytosis (RP) and multiple myeloma (MM) in bone marrow aspirates by assessment of silver-stainable nucleolar organizer regions (AgNORs). Methods: Archival cytologic smears (n = 69) from bone marrow aspirates were retrospectively investigated. Twenty cases had RP and 49 cases MM (24 low-grade, 22 intermediate-grade and 3 high-grade MM). Diagnoses were confirmed by evaluation of the corresponding bone marrow trephine biopsies. Cytologic smears were subjected to AgNOR staining using a standardized silver-staining protocol and assessed by two independent clinical histopathologists using digital image analysis. AgNOR count and area were analyzed in 100 plasma cell nuclei per sample. Results: The mean AgNOR area was found to be significantly (p < 0.001) higher in low-grade MM (mean: 23.4 µm2; range: 19.2–26.7 µm2) than in RP cases (mean: 6.2 µm2; range: 3.8–8.4 µm2). In contrast, mean AgNOR count failed to disclose significant differences between low-grade MM (mean: 5.36; range: 1–7) and RP (mean: 3.68; range: 1–6). Conclusion: Digital image analysis of the mean AgNOR area might be used as a diagnostically useful adjunct to aid objectively in the challenging differentiation between RP and MM in bone marrow aspirates.