Time-limited psychodynamic psychotherapy is garnering empirical support as an intervention for clinical depression. However, research is needed to examine the efficacy of psychodynamic approaches among patients presenting with diverse psychiatric and medical problems. This case study examined the efficacy of eight sessions of pragmatic psychodynamic psychotherapy (PPP) in treating a woman with major depression and breast cancer. Pre- to posttreatment assessment indicated significant reductions in depression and weekly assessment indicated increased environmental reward was associated with reduced depression. Secondary aims involved piloting a functional magnetic resonance imaging (fMRI) task as a neurobiological indicator of depression attenuation as a function of PPP. This assessment was conducted to explore alternative means of evaluating treatment responsiveness and addressing the problem of arbitrary metrics in measuring change. Clinical and assessment implications are discussed, with a focus on innovative approaches to evaluate treatment outcome and behavioral and neurobiological mechanisms of change associated with PPP.