The use of rituximab, a B-cell-depleting agent as a pre-emptive treatment in immune-mediated thrombotic thrombocytopenic purpura (iTTP), is the current standard of care. However, for patients refractory to rituximab or for those with contraindications, further treatment guidelines are scarce. Standard immunosuppressive or chemotherapeutic agents were used routinely in the past, but most of the data proving their efficacy are stemming from experience before the routine use of rituximab. Ciclosporin A and azathioprine seem to be effective in the pre-emptive setting, but their safety profile might limit their use. Extended or intensive rituximab administration may overcome refractoriness in some patients. New therapeutic options, such as new generation anti-CD20 antibodies like obinutuzumab or the plasma cell-directed therapy daratumumab, showed important efficacy in iTTP after rituximab failure, with a favourable safety profile. There are no available comparative studies for pre-emptive treatment options in iTTP; therefore, data from large databases and multicentre studies are essential. In this review, we summarize the possible treatment options in case of rituximab failure in iTTP and try to provide a recommendation based on available literature and our own experience.