Few studies have examined functional connectivity (FC) patterns using functional magnetic resonance imaging (fMRI) to predict outcomes in late-life depression. We hypothesized that FC within and between frontal and limbic regions would be associated with 12-week depression outcome in older depressed adults. Seventy-one subjects with major depression were enrolled in the study. A study geriatric psychiatrist performed a clinical interview and completed a Montgomery-Åsberg Depression Rating Scale (MADRS). All study participants were free of medication at baseline and had a brain fMRI scan. Using a regions of interest (ROI) atlas (including 164 ROIs), we conducted ROI-to-ROI resting-state FC analyses for each participant. In terms of treatment participants were offered sertraline initially, although in this naturalistic study, other medications were also prescribed. Subjects were evaluated every 2 weeks up to 12 weeks by the study psychiatrist, who followed a flexible, clinically based medication dosing schedule. Multivariate regression analysis was used to examine correlation between change of MADRS score over 12 weeks and baseline FC between brain regions, controlling for age, gender, mean head motion, and baseline MADRS. We found greater FC between the left inferior frontal gyrus pars triangularis and the left frontal eye field and FC of these two regions with a number of brain regions related to reward, salience, and sensorimortor function were correlated with change in MADRS score over 12 weeks. Our results highlight the important role of between inner speech-reward, attention-salience, and attention-sensorimotor network synchronization in predicting acute treatment response in late-life depression.