While there is currently no direct known cause of bile duct cancer, studies have shown that there are, in fact, several connections- ranging from liver disease to obesity- which can potentially increase the risk of developing bile duct cancer.

Like with most cancers, a person's gene pool often plays a role in who is more susceptible of contracting bile duct cancer. Certain people have DNA and proteins which causes their cells to become cancerous far faster than others. For example, research has shown that the "protein 53" tumor suppressor gene is found in almost all bile duct cancer patients; the KRAS, HER2/neu, and c-Met proteins are also under current study as influences of bile duct cancer. Heredity, however, is usually not as significant, since bile duct cancer affects people later in life, typically over the age of 65. If DNA changes do occur, then they are mostly acquired through other means. 

A strong link has also been made between bile duct cancer and inflammation of the bile duct system (cholangitis), which can similarly cause gene mutations reflective of cancer. Gall stones and bile duct stones, for instance, are both common sources of bile duct inflammation. In certain countries in Latin America, the Middle East, and Asia, parasitic infestation has also been proven to cause harmful bile duct swelling. For the latter, a parasitic worm known as a liver fluke (Clonorchis sinensis and Opisthorchis viverrini, usually) is quite endemic in infesting the bile ducts of fish-eating people, particularly in the poorest areas of Thailand, Laos, Vietnam and Cambodia; research estimates that as many as seven million people have been infected by the liver fluke throughout Southeast Asia. Although the number of bile duct cancer cases which have resulted- or will result- from this number are not clear, people who have shown persistent bile duct inflammation are at an exceptional high risk of developing bile duct cancer.

Other disorders which have been known to cause bile duct inflammation, and therefore, a higher risk of contracting bile duct cancer are: primary sclerosing cholangitis, inflammation which leads to scar tissue formation; ulcerative colitis, inflammation of the large intestine which often leads to inflammation in the bile duct; choledochal cysts, or small pockets of bile which often contain pre-cancerous cells; a disrupted flow of digestive fluids; and lastly, scar tissue which forms as a result of cirrhosis (liver damage from alcohol or hepatitis). Other liver diseases- like polycystic liver disease and Caroli syndrome- are additionally attributed to bile duct cancer. 

There is also a connection between bile duct cancer and overall health, including age and obesity. Studies have shown that people over the age of 65, for instance, are far more prone to contracting the disease. About 65% of bile duct cancer patients will be over this age, with 73 being the average age of bile duct cancer diagnosis. Overweight individuals, on the other hand, are more apt to bile duct stone and gallstone formation, which as mentioned above, show a considerable connection to bile duct cancer. Smoking, diabetes, pancreatitis, and exposure to asbestos and radioactive chemicals are potential risk factors as well, although research has not yet confirmed these. Exposure to thorotrast, however, a specific radioactive contrast agent which was used extensively until the 1950s, has shown a direct correlation.