We assessed the immune response induced in multiple sclerosis (MS) patients who had received NBI‐5788, an altered peptide ligand (APL) designed from an immunodominant region (83–99) of the neuroantigen myelin basic protein (MBP) (5, 10, or 20 mg subcutaneously weekly for 4 weeks). The mean frequency of NBI‐5788–responsive T cells (stimulation index > 3) in MS patients treated with the APL was 35.8 ± 12.8% (n = 7) compared with a mean frequency of 6.2 ± 1.3% (n = 7) for the untreated patients. The mean frequency of whole MBP–responsive T cells in MS patients treated with the APL was not significantly different from that of untreated patients (16.4 ± 5.7% vs 18.0 ± 6.3%, respectively). NBI‐5788–reactive T‐cell lines generated from NBI‐5788–treated patients exhibited an increased frequency of cross‐reactivity with MBP peptide 83–99 compared with NBI‐5788–reactive lines from control MS patients. Cytokine secretion by APL‐reactive T‐cell lines from NBI‐5788–treated MS patients was more frequently T‐helper 2–like compared with T‐cell lines from untreated MS patients. These results demonstrate that subcutaneous administration of a soluble APL based on the MBP peptide 83–99 in MS patients can induce an APL‐reactive immune response in which T lymphocytes cross‐reactive with the immunodominant neuroantigen MBP secrete anti‐inflammatory cytokines. The significant heterogeneity in immune response between individuals indicates the need for clinical laboratory correlation during the course of therapeutic trials. Ann Neurol 2000;48:758–765