Objective Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis. Background Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown. Design/Methods SPRINT‐MS was a randomized, placebo‐controlled 96‐week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three‐way interaction linear‐mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored. Results Analysis showed that there was a three‐way interaction between the time, treatment effect, and disease phenotype (P