Antigenic targets of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) paraproteins might play a role in the pathogenesis of these neoplasms. We screened a human fetal brain‐derived macroarray with the IgA or IgG containing sera of 192 consecutive MGUS and MM patients. Twenty‐nine of 192 (15.1%) paraproteins reacted with paratarg‐7, a protein of unknown function which is expressed in all human tissues. Paratarg‐7 reactivity was similarly frequent among IgA and IgG paraproteins, but all paratarg‐7 reactive IgG paraproteins belonged to the IgG3 subtype with 24/57 IgG3 (42.1%) paraproteins displaying this specificity. Sequence analysis of paratarg‐7 derived from patients having a paraprotein with specificity for paratarg‐7 revealed no differences to paratarg‐7 derived from patients with paraproteins of other specificities or healthy controls, excluding mutations or polymorphisms as a reason for its autoimmunogenicity. Similarly, Western‐blot analysis showed identical bands for paratarg‐7 derived from patients and controls. The above‐random frequency of paratarg‐7 as a paraprotein target suggests that paratarg‐7 might be involved in the development of the respective clonal proliferations. The identification of paratarg‐7 as an antigenic target enables the more detailed analysis of tumor–host interactions in these patients and their role in the pathogenesis of MM and MGUS. © 2009 UICC