INTRODUCTION: Gelatinous Heberden's nodes (HNs), also termed synovial cysts, are a common form of generalised osteoarthritis (OA). We sought to determine if HN cases at clinical presentation contained multipotential stromal cells (MSCs), and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis. METHODS: At clinical presentation, gelatinous material was extracted/extruded from the distal phalangeal joint of OA patients with HNs. From this, plastic adherent cells were culture expanded for phenotypic and functional characterisation and comparison to BM- and SF- MSCs. Mesenchymal related gene expression was studied using a custom designed Taqman Low Density Array to determine transcriptional similarities between different MSC groups and skin fibroblasts. RESULTS: In all cases, HN material produced MSC-like colonies. Adherent cultures displayed an MSC phenotype (CD29+, CD44+, CD73+, CD81+ CD90+ and CD14- CD19-, CD31-, CD34-, CD45- and HLADR-) and exhibited osteogenic, chondrogenic lineage differentiation but weak adipogenesis. Gene cluster analysis showed HN-MSCs were more closely related to SF- than normal or OA BM-MSCs with significantly higher expression of synovium related gene markers such as bone morphogenic protein 4 (BMP4), bone morphogenetic protein receptor type 1A (BMPR1A), protein/leucine-rich end leucine-rich repeat protein (PRELP), secreted frizzled-related protein 4 (SFRP4) and tumour necrosis factor alpha-induced protein 6 (TNFAIP6) (P < 0.05). CONCLUSIONS: Gelatinous HNs derived from hand OA at clinical presentation contain a population of MSCs that share transcriptional similarities with SF derived MSCs. Their aberrant entrapment within the synovial cysts may impact on their normal role in joint homeostasis.