Leukoplakia can be caused by a wide range of factors. The most common cause of leukoplakia is chronic irritation. A large number of irritants may be responsible, including:

• Tobacco products. This includes all types of tobacco products, including those that are smoked or chewed. Tobacco is responsible for the majority of cases of leukoplakia. Other plant-based chewing products such as betel, commonly used in Southeast Asia, can also cause leukoplakia.
  
  
• Long-term alcohol use. Long-term consumption of alcohol, especially among heavy drinkers, is a common cause of oral irritation that can lead to leukoplakia.
  
  
• Ill-fitting dentures or dental appliances. Dental appliances that do not fit properly can irritate the lining of the mouth and result in leukoplakia.
  
  
• Chewing the inner cheeks. Repeatedly biting or chewing the inside cheeks can injure the lining of the mouth and lead to leukoplakia.
  
  
• Rough edges inside the mouth. Sharp areas of teeth (or their restorations) can poke or irritate the mucous membrane lining of the mouth.
  
  
• Sanguinarine. This antimicrobial ingredient found in some toothpastes and mouth rinses has been associated with leukoplakia.  

Occasionally leukoplakia will appear on external female and male genitals. The cause for this is not fully understood but may involve infection with the human papilloma virus (HPV).  

Infections have been found in some leukoplakia lesions. It is not clear whether these infections cause leukoplakia, or whether they occurred after the lesion developed. Infections associated with leukoplakia include:

• Fungal infections (e.g., Candida albicans fungi, which cause thrush)
  
  
• Viral infections (e.g., HPV, which may cause genital warts)
  
  
• Bacterial infections (in particular the sexually transmitted disease syphilis)

Hairy leukoplakia develops as the result of reactivation of the Epstein-Barr virus that can cause mononucleosis. This virus is usually contracted during childhood, often without the child displaying any symptoms. It may become reactivated in adulthood due to an immune system deficiency, usually human immunodeficiency virus (HIV) infection.

Some people may be more susceptible to leukoplakia than others. For example, leukoplakia occurs more often among men than women. However, this may be due to the tendency for men to use tobacco and consume alcohol more often than women. However, women who develop leukoplakia may be more likely to develop oral cancer. Leukoplakia is also more likely to occur in people over the age of 40.

Given the multiple irritants that cause leukoplakia, tobacco and alcohol use are the primary factors that place a person at risk of developing the condition. In addition, people with ill-fitting dental appliances or sharp teeth (or restorations) may also be at risk of developing leukoplakia.