When the spores of C. immitis are inhaled, they can become lodged in the lungs, divide, and cause localized inflammation. This is known as acute or primary coccidioidomycosis. The disease is not spread from one person to another. Approximately 60% of people who are infected exhibit no symptoms (asymptomatic). In the other 40%, symptoms appear 10–30 days after exposure. These symptoms include a fever which can reach 104°F (39.5°C), dry cough, chest pains, joint and muscle aches, headache, and weight loss. About two weeks after the start of the fever, some people develop a painful red rash or lumps on the lower legs. Symptoms usually disappear without treatment in about one month. People who have been infected gain partial immunity to reinfection.

The chronic form of coccidioidomycosis normally occurs after a long latent period of 20 or more years during which the patient experiences no symptoms of the disease. In the chronic phase, coccidioidomycosis causes lung abscesses that rupture, spilling pus and fluid into the lungs, and causing serious damage to the lungs. The patient experiences difficulty breathing and has a fever, chest pain, and other signs of pneumonia. Medical treatment is essential for recovery.

In its disseminated form, coccidioidomycosis spreads to other parts of the body including the liver, bones, skin, brain, heart, and lining around the heart (pericardium). Symptoms include fever, joint pain, loss of appetite, weight loss, night sweats, skin lesions, and difficulty breathing. Also, in 30–50% of patients with disseminated coccidioidomycosis, the tissue coverings of the brain and spinal cord become inflamed (meningitis).