Major depressive disorder (MDD) is the leading cause of disability in the developed world, yet broadly effective treatments remain elusive. The primary aim of this pilot study was to investigate the efficacy of mindfulness-based cognitive therapy (MBCT) monotherapy, compared to sertraline monotherapy, for patients with acute MDD. This open-label, nonrandomized controlled trial examined a MBCT cohort (N = 23) recruited to match the gender, age, and depression severity of a depressed control group (N = 20) that completed 8 weeks of monotherapy with the antidepressant sertraline. The 17-item clinician-rated Hamilton Depression Severity Rating Scale (HAMD-17) was the primary outcome measure of depression to assess overall change after 8 weeks and rates of response and remission. The 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) was the secondary outcome measure to further assess depression severity. Both cohorts were demographically similar and showed significant improvement in depression ratings. No difference was found in the degree of change in HAMD-17 scores (t(34) = 1.42, p = 0.165) between groups. Secondary analysis showed statistically significant differences in mean scores of the QIDS-SR16 (t(32) = 4.39, p < 0.0001), with the MBCT group showing greater mean improvement. This study was limited by the small sample size and non-randomized, non-blinded design. Preliminary findings suggest that an 8-week course of MBCT monotherapy may be effective in treating MDD and is a viable alternative to antidepressant medication. Greater changes in the self-rated QIDS-SR16 for the MBCT cohort raise the possibility that patients derive additional subjective benefit from enhanced self-efficacy skills.