Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and potential extra-articular manifestations. This review compares the presentation and treatment response between anti-citrullinated protein antibodies (ACPA)-positive and ACPA-negative RA patients. The incidence of seronegative RA (rheumatoid factor (RF)-negative and ACPA-negative) has increased in recent decades, emphasizing the need for new diagnostic biomarkers.Diagnostically, ACPA is highly specific for RA, yet many patients remain ACPA-negative. The absence of RF and ACPA in RA should trigger further analysis to test alternative diagnosis, in particular when new symptoms arise. Emerging biomarkers like anti-PAD4 and anti-CarP antibodies provide additional diagnostic value, identifying some ACPA-negative patients. Clinically, ACPA-negative patients often exhibit higher disease activity at diagnosis, with more swollen joints and elevated CRP levels. They also tend to have fewer pulmonary and ocular manifestations compared to ACPA-positive patients. Radiographically, ACPA-positive patients are at a higher risk for joint erosions over time.Response to treatment also differs according to ACPA status. Abatacept and rituximab have demonstrated greater efficacy in ACPA-positive patients, showing better disease activity control and higher treatment retention rates. Continuous re-evaluation is crucial for ACPA-negative patients, especially when first-line treatments like methotrexate are ineffective, to rule out RA mimickers and adjust the treatment approach accordingly.These findings underscore the importance of personalized treatment strategies in RA management.