BACKGROUND: Rifampicin is a first-line anti-tuberculosis drug, but it may cause severe allergic adverse reactions. CASE PRESENTATION: This case report describes an unusual and severe adverse reaction to rifampicin in a 53-year-old male patient with pulmonary tuberculosis. The patient developed intense systemic pain within 4 hours of rifampicin administration, affecting multiple organs and joints, without typical allergic manifestations, such as fever or rash. The pain progressively worsened over three consecutive days of treatment, reaching its peak intensity (NRS score 8/10) on the third day with pain duration extending from 3 to 8 hours. The severe pain was characterized as sharp and burning in nature, significantly impacting the patient's daily activities and mobility. A subsequent rifampicin challenge test (single dose 0.45g) confirmed the causal relationship by reproducing identical severe pain symptoms. The Naranjo adverse drug reaction probability scale yielded a score of 7, indicating a "probable" causal relationship. Notably, the patient exhibited underlying autoimmune abnormalities (positive ANA and elevated ESR), which may have contributed to the severity of the reaction through enhanced inflammatory responses and altered pain mechanisms. The symptoms completely resolved upon rifampicin discontinuation, and alternative treatment with levofloxacin proved successful with no pain recurrence during the fourmonth follow-up period. CONCLUSION: This case highlights a previously unreported presentation of rifampicin hypersensitivity and emphasizes the importance of careful risk assessment in patients with autoimmune features before initiating rifampicin therapy.