A 21-year-old has painful lesions in the mouth with fever. What is the most likely diagnosis?

The most likely diagnosis in this scenario is primary herpetic gingivostomatitis. This condition is characterized by the appearance of painful vesicular lesions in the oral cavity and typically presents with systemic symptoms such as fever, particularly in younger patients.

Primary herpetic gingivostomatitis is caused by the herpes simplex virus, often HSV-1. The initial infection usually occurs in children or young adults, and it is marked by multiple painful ulcers, swollen gums, and the aforementioned fever due to the body's immune response to the viral infection.

In contrast, recurrent herpes labialis primarily involves the lips and presents as cold sores without the systemic symptoms associated with primary infection. Aphthous ulcers are generally not accompanied by fever and occur as small, painful sores but are distinct from the vesicular lesions seen with herpes. Candidiasis, or oral thrush, can cause discomfort but typically presents with white patches rather than vesicular lesions, and fever is not a common feature unless there is a severe underlying immunocompromised state.

Thus, the combination of painful oral lesions along with fever strongly indicates primary herpetic gingivostomatitis as the most likely diagnosis.