Estimation of causal effects from observational data is a primary goal of epidemiology. The use of multiple methods with different assumptions relating to exchangeability improves causal inference by demonstrating robustness across assumptions. We estimated the effect of antiretroviral therapy (ART) on mortality in rural KwaZulu-Natal, South Africa, from 2007 to 2011, using 2 methods with substantially different assumptions: the regression discontinuity design (RDD) and inverse-probability-weighted (IPW) marginal structural models (MSMs). The RDD analysis took advantage of a CD4-cell-count-based threshold for ART initiation (200 cells/muL). The 2 methods yielded consistent but nonidentical results for the effect of immediate initiation of ART (RDD intention-to-treat hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.35, 1.26; RDD complier average causal effect HR = 0.56, 95% CI: 0.41, 0.77; IPW MSM HR = 0.49, 95% CI: 0.42, 0.58). Although RDD and IPW MSM estimates have distinct identifying assumptions, strengths, and limitations in terms of internal and external validity, results in this application were similar. The differences in modeling approaches and the external validity of each method may explain the minor differences in effect estimates. The overall consistency of the results lends support for causal inference about the effect of ART on mortality from these data.