The present study examined the relationship between religiosity/spirituality and treatment response to antidepressant medication (citalopram). One-hundred and forty-eight Caucasian and African-American adults with uncomplicated major depression were treated with citalopram (20-60mg/day) over an 8-week period in a prospective multi-site clinical trial. Treatment response was assessed weekly with the Hamilton Rating Scale for Depression. Religiosity (i.e., religious behaviours) and spirituality (i.e., spiritual well-being) were assessed at Week 3. No significant associations between spirituality and treatment response were found; however, there was a strong curvilinear relationship between religiosity and treatment response. Compared to lower or higher levels of religiosity, a moderate level of religiosity was significantly associated with a higher likelihood of remission and greater reduction in severity of depression. This association was independent of social support, ethnicity, gender, education, and baseline depression severity. A moderate amount of religiosity appears to be independently associated with an enhanced treatment response to citalopram.