A 38 years female presented with arthralgia, dyspnoea, progressive proximal muscle weakness, seizures, weight loss, dysphagia, alopecia, and dryness of the eyes and mouth with tightening of the skin. Psychiatric evaluation revealed major depression. She had oral ulcers, tightening of the skin of the hands with restricted mouth opening, and proximal muscle weakness. Mixed connective tissue disorder (MCTD) with predominant polymyositis and neuropsychiatric manifestations was diagnosed as the patient had anti-RNP positive with significantly raised muscle enzymes. This case is unique because major depression in MCTD is rarely documented, severe polymyositis is a rarity and ANA was negative but characteristic anti-RNP antibody was positive.