BACKGROUND: Targeted therapy combined with anti-programmed cell death 1 immunotherapy (TP) and trifluridine/tipiracil (TAS-102) combined with bevacizumab (TB) are two common therapies for patients with late-line therapy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). However, it is still unclear which therapy can bring better prognosis. AIM: To evaluate the effectiveness and safety of TP TB as the late-line regimen for MSS mCRC in the real world. METHODS: This is a dual-center retrospective cohort study conducted in Peking University First Hospital and Jilin Cancer Hospital. Patients with MSS mCRC who had received at least the second line treatment were eligible. Propensity score (PS) would be calculated to balance the baseline characteristics of two cohorts. Progression-free survival (PFS) was set as the primary endpoint. The Kaplan-Meier method and Cox proportional hazard model were used to evaluate PFS and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Landmark analysis was performed to create segmented survival curves, studying the impact of treatment regimen on prognosis during different follow-up periods. RESULTS: Between July 2019 and March 2025 (data cutoff), 127 eligible patients were enrolled, with 88 and 39 patients assigned to the TP and TB cohorts, respectively, based on treatment allocation. At a global median follow-up of 9.73 months, the crude median PFS was 3.9 months (95%CI: 3.03-5.53) in the TP cohort 4.17 months (95%CI: 2.87-5.6) in the TB cohort, yielding a nonsignificant HR of 1.43 (95%CI: 0.94-2.18, = 0.092; TB as reference). Multivariate Cox regression analysis, adjusted for sex, age > 60 years, Eastern Cooperative Oncology Group performance status, mutation, primary tumor location (left right), number of metastatic organs (liver/lung), and treatment line (≥ 3 line), demonstrated an adjusted HR of 1.23 (95%CI: 0.80-1.88, = 0.348). PS-based analyses using three methodologies: Inverse probability weighting, PS matching (post-matching = 55 30), and PS-adjusted multivariate Cox regression. These analyses revealed consistent nonsignificant trends favoring TB, with HRs for TP of 1.26 (95%CI: 0.76-2.10, = 0.077), 1.42 (95%CI: 0.87-2.34, = 0.164), and 1.26 (95%CI: 0.76-2.10, = 0.367), respectively. Notably, landmark PFS analyses at 90, 120, and 150 days demonstrated a significantly higher proportion of TP patients maintaining disease control beyond these timepoints ( = 0.048, 0.031, and 0.035, respectively), suggesting sustained clinical benefits in TP responders. CONCLUSION: TP and TB demonstrated similar PFS in both crude and PS-adjusted analyses. However, patients who derived benefits from TP therapy exceeding 90 days showed more sustained clinical advantages compared to TB. Our study suggests that for patients with MSS mCRC who respond to TP therapy in later-line treatments, this regimen could provide additional prolonged clinical benefits, which warrants further validation through large-scale cohort investigations.