For people with no prior contact with HSV-1 or 2, initial infection is characterized both by systemic (whole body) as well as by local symptoms and signs. Generalized symptoms include: fever, malaise, muscle aches, and decreased appetite. Local symptoms are described below.

Prior to the appearance of blisters, the infected individual may experience increased skin sensitivity, tingling, burning, itching, or pain at the site where the blisters will appear.

The skin may redden, and then erupt with multiple small blisters (vesicles) filled with clear, straw-colored fluid. The blisters then break, resulting in shallow ulcers that are very painful. These ulcers eventually crust over and slowly heal over a period of 7 to 14 days.

The outbreak may be accompanied by enlargement and tenderness of lymph nodes in the groin. Women also may develop vaginal discharge and painful urination. Men develop painful urination if the lesion is near the opening of the urethra.

Once a person is infected, the virus hides within nerve cells, making it difficult for the immune system to detect and destroy it. Within the nerve cells, the virus may remain dormant for an extended time, a period called "latency."

The infection may reactivate at any time, at which point the individual once again develops painful blistering over the genitals, anus, inner thigh, or mouth. A variety of events may trigger latent infection to become active, including mechanical irritation, stress, menstruation, and fatigue.

Recurrent attacks can occur as seldom as once per year, or so frequently that the symptoms seem continuous. Recurrent infections in men are generally milder and of shorter duration than those experienced by women.

• Viral culture of blister fluid from lesion positive for herpes simplex virus. Herpes simplex virus may grow within 2-3 days. If this test is positive, it is almost 100% accurate, especially if the fluid is from an initial blister rather than a recurrent blister. Since viruses can be hard to grow, it is often negative, even when herpes is present.
• Detection of the herpes simplex virus DNA by PCR from the blister fluid. The blister fluid contains human cells and virus particles. PCR is a technique that detects small amounts of DNA and could tell you if the herpes virus was present in the blister.
• Tzanck test of skin lesion may show results consistent with herpes virus infection. This test involves staining human cells within the blister fluid with a dye. If the cells from the fluid contain viral particles, they become visible. However, the test cannot determine which strain of virus is present in the blister.

Recently developed antibody tests can determine if the person has HSV-1 or HSV-2. These tests can also tell if the individual has ever been exposed to either of these strains in the past (IgG test) or was just recently exposed to one of them (IgM test).