Background: An increased incidence of brain white-matter hyperintensities has been described in major depressive disorder, but the impact of such hyperintensities on treatment outcome is still controversial. Aims: To investigate the relationship of brain white-matter hyperintensities with cardiovascular risk factors and with treatment outcome in younger people with major depressive disorder. Method: We assessed brain white-matter hyperintensities and cardiovascular risk factors in 84 people with major depressive disorder prior to initiating antidepressant treatment. We also assessed hyperintensities in 35 matched controls. Results: We found no significant difference in the prevalence of white-matter hyperintensities between the depression and the control groups. Left-hemisphere subcortical hyperintensities correlated with lower rates of treatment response. We found no correlation between global hyperintensity measures and clinical outcome. Brain white-matter hyperintensities correlated with hypertension and age and with total cardiovascular risk score. Conclusions: Subcortical white-matter hyperintensities inthe left hemisphere (but not in other brain areas) may be associated with poor response to antidepressant treatment in major depression.