Abstract Abundant mRNA expression for a proliferation-inducing ligand (APRIL) from tumor necrosis factor (TNF) family is observed in many solid tumors. Here, we analyzed in situ the cellular source of APRIL in human solid tumors with anti-APRIL antibodies. In most cases, neutrophils present in the tumor stroma constituted the main source of APRIL. In cutaneous lesions such as melanoma or basal cell carcinoma, tumor-adjacent keratinocytes also produced APRIL. APRIL production by tumor cells themselves was a rare event, only observed in urothelial bladder cancer and squamous cell carcinoma. Detailed analysis revealed that APRIL dissociated from producing cells, and secreted APRIL was retained in the tumor lesions. A direct binding onto tumor cells via heparan sulfate proteoglycans (HSPG) was observed in in vitro experiments and confirmed in situ. Taken together, our analysis indicates a potential role for HSPG/APRIL interactions in the development of solid tumors.