Rationale Although mild and rapidly improving stroke symptoms are the most common first stroke presentation, this group has been understudied in acute stroke trials. Observational and retrospective studies suggest residual disability in one third of patients. Aims To elucidate long-term outcomes of patients with mild and rapidly improving stroke, evaluate the predictors of outcome, and examine the association with alteplase treatment. Sample size The initial estimate of 2650 participants to detect a 9% difference in non-disabled 90-day outcomes between alteplase-treated and untreated participants was revised to 2000 after a pre-planned re-estimation based on actual treatment rates. Methods and design Prospective observational study of patients with mild ischemic stroke (NIHSS ≤ 5) or rapidly improving stroke symptoms evaluated within 4.5 h from onset. Outcomes The primary outcome is the proportion of patients with modified Rankin Scale (mRS) ≥ 2 at 90 days; the primary safety outcome is symptomatic hemorrhagic transformation within 36 h among those treated with alteplase. Secondary outcomes include the 90-day Barthel Index, Stroke Impact Scale 16, European Quality of Life scale, mRS at 30 days, and 30- and 90-day mortality. Discussion MaRISS will define outcomes and their predictors and clarify the effects of alteplase in patients with mild and rapidly improving stroke symptoms, providing clinicians with important information to manage this population.