Objectives: To compare the effectiveness of a 2nd TNF inhibitor (TNFi), Tocilizumab (TCZ) and Rituximab (RTX), measured by drug retention and by response rates, in RA patients after discontinuing a first-line TNFi and to clarify the reasons and predictors for discontinuation of a second-line biologic. Material and Methods: Non-interventional prospective study of RA patients exposed to a 2nd TNFi, TCZ or RTX after previous TNFi discontinuation using real-world data from Reuma.pt database. Drug retention was estimated using Kaplan-Meier analysis and Cox models. Crude and LUNDEX adjusted response rates were evaluated at 6 months, 1 and 2 years and reasons for discontinuation were compared according to biologic class. Results: In total, 643 patients were included, 88.8% females, with a mean age of 59.4±12.8 years. Of those, 390 (60.7%) initiated a 2nd TNFi, 147 (22.9%) TCZ and 106 (16.5%) RTX. Drug retention was significantly greater among patients who initiated TCZ (76.4±4.3 months) or RTX (80.8±4.8 months), compared with those who initiated a 2nd TNFi (52.7±2.6 months) (log rank test, p < 0.001). In the adjusted Cox model, hazards of discontinuation were significantly lower for TCZ (HR 0.39, 95% CI 0.23-0.64, p < 0.001) and RTX (HR 0.42, 95% CI 0.25-0.72, p=0.001). Smokers had a significantly higher risk for discontinuation (HR 2.43, 95%CI 1.50-3.95, p < 0.001) as well as patients with higher HAQ at baseline (HR 1.51, 95%CI 1.14-2.00, p=0.004). The proportion of patients in remission or low disease activity according to Clinical Disease Activity Index (CDAI) at 6 months, 1 and 2 years was, respectively, 46.5%/50.0%/61.2% for TNFi, 52.9%/53.6%/ 69.2% for TCZ and 37.7%/48.0%/50.0% for RTX. After LUNDEX adjustment, response rates were, respectively, 33.0%/31.0%/31.8% for 2nd TNFi, 42.8%/41.8%/53.3% for TCZ and 32.0%/39.4%/39.0% for RTX. The main reasons for discontinuation were inefficacy for 2nd TNFi and RTX and adverse events for TCZ (p < 0.001). Conclusions: Our findings showed a significantly higher drug retention for TCZ and RTX, compared with 2nd TNFi, and similar persistence among TCZ and RTX, in patients who discontinued a first-line TNFi. These data corroborate the notion that switching to a biologic with a different mode of action is more effective than to a second TNFi.