The American dog tick, is a species of tick that is known to carry bacteria responsible for several diseases in humans, including Rocky Mountain spotted fever and tularemia (Francisella tularensis). It is one of the most well-known of hard ticks. D. variabilis is not the primary vector for Lyme disease, which is caused by Borrelia burgdorferi. But a study in Santa Cruz, California, found Borrelia burgdorferi in D. variabilis.

The primary vector for Borrelia burgdorferi is the deer tick Ixodes scapularis in Eastern parts of the United States, and Ixodes pacificus in California and Oregon. Dermacentor variabilis may also carry Anaplasma phagocytophilum, the causative agent of HGE (human granulocytic ehrlichiosis), and Ehrlichia chaffeensis, the causative agent of HME (human monocytic ehrlichiosis).

Dermacentor ticks may also induce tick paralysis by elaboration of a neurotoxin that induces rapidly progressive flaccid quadriparesis similar to Guillain-Barr syndrome. The neurotoxin prevents presynaptic release of acetylcholine from neuromuscular junctions.