A 46-year-old female who complained of dyspnea on exertion was diagnosed with mixed connective tissue disease (MCTD) based on interstitial pneumonia on chest computed tomography scan, a positive result for anti-ribonucleoprotein antibodies, and systemic lupus erythematosus-like physical findings such as swelling of the fingers, polyarthritis, and facial erythema. Oral prednisolone (30 mg/day) and intravenous cyclophosphamide (500 mg/kg body weight) improved both physical symptoms and radiographic findings quickly. However, 10 days after the start of treatment, she developed pyrexia with mild arthralgia and myalgia, and was urgently admitted to the hospital. Pancytopenia and elevated aspartate aminotransferase and lactate dehydrogenase levels were observed, despite no worsening of the interstitial pneumonia. These findings suggested the possibility of macrophage activation syndrome due to uncontrolled MCTD. Methylprednisolone pulse therapy (1,000 mg/day) was given, followed by the addition of intravenous cyclophosphamide (500 mg/kg body weight) and oral prednisolone (60 mg/day). After the treatment, her blood counts recovered, and her fever, arthralgia, and myalgia improved. Early close examination is important when MCTD worsens, as it has a variety of symptoms and can be severe.