Prophylactic anti‐D is a very safe and effective therapy for the suppression of D‐immunization and prevention of haemolytic disease of the foetus and newborn. The primary mode of action of anti‐D is rapid clearance of fetal D‐positive red cells from the maternal circulation, mediated by interactions with immunoglobulin G Fc receptors on macrophages in the spleen. Many anti‐D monoclonal antibodies (mAb) have been produced by a variety of methods. Twelve anti‐D mAbs were tested in eight studies for their ability to mediate clearance of autologous red cells, and 13 antibodies studied in seven trials of the clearance of D‐positive red cells injected into D‐negative subjects. Antibodies produced by human B‐cell lines, mouse–human heterohybridomas and Chinese hamster ovary cells varied in their activity with none being quite as effective as polyclonal anti‐D. However, clearance mediated by recombinant anti‐D produced by rat YB2/0 cells was extremely rapid, faster than polyclonal anti‐D, but with haemolysis and some hepatic accumulation of red cells observed in one study. Two human anti‐D mAbs prevented D‐immunization. In contrast, anti‐D mAbs from heterohybridomas increased the incidence and rapidity of anti‐D responses. It is hypothesised that unnatural glycosylation of monoclonal anti‐D produced by some cell lines may have caused these unexpected results. In some antibodies, unusual oligosaccharides on anti‐D may have affected binding to Fc receptors resulting in reduced red cell clearance. For others, non‐human glycoforms of anti‐D might have bound to innate immune recognition molecules promoting pro‐inflammatory reactions. These extensive data on the clinical activity of monoclonal anti‐D produced by cell lines derived from four species will inform the future development of monoclonal anti‐D for RhD prophylaxis.