The key diagnostic criterion for Morgellons Disease is the presence of unusual filaments beneath unbroken skin or projecting from skin. There are no diagnostic laboratory tests specifically targeting Morgellons Disease. Research suggests that Morgellons Disease is a manifestation of Lyme disease, and if Morgellons Disease is suspected in a patient, he/she should therefore be tested for Lyme disease. Unfortunately, however, there is no test currently available that is 100% accurate for diagnosing Lyme disease. Both false positive and false negative results can occur, with the latter being far more common. Ultimately, a Lyme diagnosis is a clinical diagnosis to be made by a qualified physician or other healthcare provider, based on symptoms and patient history with test results used as tools to aid in the diagnosis. Lyme serologic testing at many laboratories fails to detect antibodies at levels high enough to be interpreted as positive by the CDC surveillance criteria. Consequently, Lyme disease testing at laboratories specializing in tick-borne diseases is recommended. A physician or other qualified healthcare provider must sign a requisition for Lyme disease testing, and a physician or other qualified healthcare provider knowledgeable about Lyme disease should be consulted for interpretation of test results and for the diagnosis and treatment of Lyme disease.

Not a lot is known about the genetic diversity of spirochetes associated with Morgellons Disease. Some laboratories offer testing based on several strains of Bb, including European strains and other related strains. In addition to spirochetal infection, ticks may carry other organisms that co-infect the patient at the time of a tick bite. Patients who have been diagnosed with Lyme disease should be tested for tickborne co-infections. The most common laboratory tests for Lyme disease are serologic tests for antibodies against Bb. Other tests include Bb antigen detection, PCR detection of Bb DNA, lymphocyte transformation tests (LTT), and culture of spirochetes. Elevated complement C4a levels and decreased CD57 natural killer cell levels may be associated with chronic Lyme disease. These tests may aid physicians in determining a Lyme disease diagnosis. Research studies have detected the bacteria Borrelia in every single Morgellons Disease study subject even though most patients have negative serology for Lyme disease.