According to international recommendations, the selection of the biologic disease modifying anti-rheumatic drug (bDMARD) for rheumatoid arthritis (RA) is mainly left to the clinician's preference. We analyzed the real-life factors influencing the first-line choice or the switching strategy, focusing on the prescription of abatacept (ABA) or tocilizumab (TCZ) compared to TNFα inhibitors (TNFi). Patients enrolled in the Lombardy Rheumatology Network (LORHEN) Registry after January 1, 2010, when all considered bDMARD agents were available, were included. The population was divided into Bfirst-^and Bsecond-line^bDMARD. We included 1910 patients (first line n = 1264, second line n = 646). Age was higher in ABA or TCZ vs TNFi treated patients (p < 0.0001). Positive latent tuberculosis screening was associated with first-line ABA (p = 0.002). Methotrexate (MTX) combination therapy was lower in the TCZ group (p = 0.02). The type (dyslipidemia, hypertension, pulmonary disease) and the number of comorbidities influenced the choice towards ABA (p = 0.01). Multinomial logistic regression demonstrated that a second-line treatment, higher age, dyslipidemia, pulmonary disease, other comorbidities, and extraarticular RA manifestations were associated with ABA compared to TNFi. TCZ was associated with a second-line treatment, higher age, and more severe disease activity. Stopping the first bDMARD due to adverse events (AE) influenced the choice towards ABA. In real life, higher age and comorbidities influence the choice towards ABA and TCZ compared to TNFi. ABA was preferred in case of suspension of previous treatments due to AE. After failing a first-line TNFi, swapping to a different mechanism of action is more common.