Abstract A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies.