Infliximab (IFX) is an anti-tumor necrosis factor-alpha antibody used to treat inflammatory joint diseases. Infusion reactions (IR) can occur during and after intravenous administration and often require discontinuation of IFX therapy. This retrospective study aimed at evaluating the incidence of IR in patients with joint inflammatory diseases receiving IFX with and without premedication. Clinical charts of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients receiving IFX from January 2002 to December 2014 were reviewed. Patients receiving only one premedication protocol over time were enrolled and clustered based on the type of premedication as follows: group 1 received no premedication; group 2 received paracetamol, esomeprazole, hydrocortisone, and chlorpheniramine maleate; group 3 received paracetamol, hydoxyzine, ranitidine, and 6-methylprednisolone. Adverse events were recorded during the infusion, in the following hours and at control visits. The charts of 105 patients treated with IFX were selected. IR were observed in 23/51 patients of group 1, in 7/35 patients of group 2, and none of 19 patients in group 3. IR incidence was significantly lower in the second (p = 0.021) and third (p < 0.001) compared to the first group. The incidence of IR was significantly lower in group 3 than group 2 (p < 0.043). Moreover, patients in group 1 had a relative risk of developing an IR 2.5 times higher than group 2. In our experience, the use of premedication significantly reduced the number of IR to IFX. In particular, the combination of paracetamol, hydroxyzine, 6-methylprednisolone and ranitidine was more efficacious than paracetamol, esomeprazole, hydrocortisone, and chlorpheniramine maleate combination protocol.