Based on the clinical and microscopic changes associated with papillomatosis, a virus has always been considered its most likely cause. Recent research findings have suggested that pieces of the genetic material (DNA) from a papillomavirus can be detected in cells from some birds with papillomatosis. Other research has shown some papillomatous lesions contain herpesvirus-like particles or pieces of Pacheco's disease virus (an avian herpesvirus). Many affected birds also have antibodies to Pacheco's disease virus. It is most likely that papillomatosis is caused by a papillomavirus and that Pacheco's disease virus co-infects the damaged cells.

If papillomatosis is caused by a papillomavirus, it is likely that it will behave similarly to papillomaviruses in other species. Once the papillomavirus takes over a cell, it causes the cell to undergo cancerous changes resulting in a thickening of the skin and development of a mass. In humans, some papillomaviruses have been shown to be associated with cancerous changes in the mouth, alimentary tract and reproductive tract.

The factors associated with development of papillomatosis are unconfirmed. If it is proven to be infectious, which is highly likely, it is probable that birds are exposed through direct contact with an infected bird or through contact with a contaminated surface (perch, enclosure, table, food bowls, etc). If a papillomavirus is involved, these viruses are considered to be relatively stable when outside of the host. If a herpesvirus is involved, these viruses tend to be relatively unstable when outside of the host. Cool, moist conditions and freezing will preserve the infectivity of most viruses.

Clinical signs in birds with papillomatosis generally occur when the mass interferes with swallowing, digestion or defecation. This disease should be suspected in birds that are straining to defecate, have putrid smelling excrement, chronic bad breath, recurrent gastrointestinal problems, cloacal prolapse or blood-tinged excrement. Internal papillomatosis is usually associated with chronic weight loss and regurgitation and can mimic the signs of proventricular dilatation disease.

While the data varies among studies, papillomatosis seems particularly common in macaws and hawk-headed parrots. However, the disease has been diagnosed in many other psittacine birds, including Amazon parrots, conures, cockatiels and African grey parrots.

The tendency of birds with papillomatosis to develop cancer of the pancreas or liver would suggest that cloacal or oral lesions may be caused by a virus that can transform infected cells.