Over the past 2 decades, rituximab, bortezomib, and bendamustine have been approved to treat mantle-cell lymphoma (MCL). To date, few studies have evaluated the comparative effectiveness of these novel agents. Therefore, this study evaluated the comparative effectiveness of those novel agents in elderly patients newly diagnosed with MCL.All newly diagnosed MCL patients aged 66 or older were identified from Surveillance, Epidemiology, and End Results Program (SEER)-Medicare databases from 1999 to 2013. Patients were categorized into 4 groups on the basis of their first-line treatment regimens: chemotherapy alone, rituximab ± chemotherapy, bortezomib ± chemotherapy, and bendamustine ± chemotherapy. Multivariable proportional hazard regressions with 1-year follow-up from treatment were performed to compare the all-cause, MCL-specific, and noncancer mortality rates. Sensitivity analyses using propensity score-adjusted and instrumental variable-adjusted regressions were also conducted.A total of 1215 MCL patients were included. The bortezomib group was not included in the primary analyses because of the small sample size (n = 24). On multivariable analyses, the rituximab group showed significant decrease in both 1-year all-cause mortality (hazard ratio [HR] = 0.38, 95% confidence interval [CI], 0.25-0.59) and MCL-specific mortality (HR = 0.38; 95% CI, 0.24-0.60) compared to the chemotherapy-alone group. The bendamustine group showed significant decrease in 1-year MCL-specific mortality (HR = 0.49; 95% CI, 0.24-0.99) compared to the chemotherapy-alone group. The results from sensitivity analyses were similar to those from primary analyses.For elderly patients with newly diagnosed MCL, rituximab-based regimen and bendamustine-based regimen as first-line treatment significantly decreased 1-year mortality rates compared to chemotherapy alone.