Purpose Among HIV-infected persons, antiretroviral therapy (ART) and depression are strongly associated with mortality. We estimated reductions in 5-year mortality in Women's Interagency HIV Study participants under plausible hypothetical increases in ART initiation and reductions in depression (CES-D score≥16). Methods We followed 885 ART-naïve Women's Interagency HIV Study participants for 5 years from their first study visit after April 1998 to death or censoring. We used the parametric extended g-formula to estimate cumulative mortality under the natural course (NC) and alternative exposure distributions. Results Baseline prevalence of depression was 52% and 62% initiated ART by 5 years. Compared with mortality under NC (13.2%), immediate ART and elimination of 36% or 67% of depressive episodes were associated with risk differences (RDs) of −5.2% (95% CI: −7.7%, −2.6%) and −5.7 (95% CI: −8.7, −2.7). Compared with immediate ART and NC for depression, additionally eliminating 67% of the depressive episodes was associated with RD = −1.6 (95% CI: −3.9, 0.8). Compared with 5-year mortality under NC for ART and elimination of 67% of depression, also initiating ART immediately was associated with RD = -2.6 (95% CI: -5.0, -0.3). Conclusions Increasing ART initiation and reducing depression were associated with moderate reductions in 5-year mortality among HIV-infected women.