Summary Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion‐weighted imaging (DWI) is a magnetic resonance imaging‐technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI‐parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro‐vessel density (P < 0·001 respectively). ADC was significantly different between patients and controls (P < 0·01) and before and after systemic therapy (P < 0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non‐invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work‐up to assess tumour burden.