ObjectivePerform a secondary analysis examining the efficacy of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for depression symptom responses, and explore changes in potential target mechanisms. DesignSecondary analysis of a randomized controlled trial with convenience age subsamples (younger (20–49 year; n = 52) versus and older (50–71 years; n = 35)). SettingCommunity mental health clinics. ParticipantsEighty-seven adults with serious mental illness. InterventionTranS-C versus treatment as usual (TAU). MeasurementsOutcomes were depression symptoms (Quick Inventory of Depression Symptoms), insomnia symptoms (Insomnia Severity Index), and objective sleep-wake rhythm measures (interdaily stability and relative amplitude). ResultsDepression response rates (≥50% symptom reductions) were higher in the TranS-C (35.0%) than the TAU (8.8%) group 6-months postintervention (χ2 = 10.3, p = 0.001). There was a medium effect of TranS-C versus TAU on depression symptoms 6-months postintervention (Cohen's d = −0.40, 95% confidence interval (CI): −0.81, 0.01). In both age groups, there were large treatment effects on insomnia symptoms post-treatment (Cohen's d >0.90). In the older subsample, there were additionally medium treatment effects on post-treatment interdaily stability (Cohen's d = 0.60, 95% CI: −0.11, 1.61). Post-treatment reductions in insomnia symptoms correlated with depression symptom reduction 6-months later in the younger subsample (Spearman rho = 0.59, n = 20, p = 0.008). In older adults, postintervention increases in interdaily stability correlated with depression symptom reductions 6-months later (Spearman rho = −0.52, n = 15, p = 0.049). ConclusionConfirmatory trials are needed, given the low age-specific sample sizes here, to determine if TranS -C's produces durable depression responses by increasing sleep-wake rhythm stability in older adults and improving insomnia symptoms in younger adults. Brief article summaryThe authors evaluated preliminary efficacy of a behavioral intervention that targets sleep/sleep-wake rhythms, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C), for depression symptoms in people with serious mental illness. TranS-C was associated with higher depression response rates than treatment as usual 6-months postintervention. The degree of depression symptom response 6-months later was related to the degree of treatment phase improvements in interdaily stability (in older adults) and reduction in insomnia severity (in younger adults).A pragmatic nonpharmacologic intervention, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction, has preliminary efficacy for improving sleep-wake factors and depression symptoms.