The mainstay of clinical screening for FIV infection is detection of circulating antibodies against FIV. Because FIV produces a persistent infection from which few cats recover, detection of FIV-specific antibodies in blood has been considered to be a reliable indicator of infection. In-house immunochromatic lateral flow antibody tests are commonly used for screening cats, and Western blot (WB) or IFA antibody tests are recommended for confirmation of infection. Antibody tests can test "positive" in kittens that have acquired anti-FIV antibodies by passive transfer in colostrum, but will turn negative when maternal antibody wanes. Some cats fail to produce detectable antibodies against FIV following infection, and will have false-negative results on antibody tests.

Although Fel-O-Vax FIV® is a scientific breakthrough in lentiviral immunoprophylaxis, its use will interfere with the currently licensed FIV-antibody diagnostic tests. Vaccinated cats produce antibodies within a few weeks of vaccination that are indistinguishable from those used to diagnose FIV infection. Although antibody titers are lower in vaccinated cats than in naturally infected cats, vaccine-induced antibodies persist for more than a year. These antibodies are also passed to kittens that nurse on vaccinated queens, and passively acquired vaccine-associated antibodies persist past the age of weaning in >50% of kittens. Cats may have FIV antibodies due to vaccination against FIV, infection with FIV, or both.

Alternatives to antibody testing have been proposed for discriminating FIV-infected cats from vaccinated cats. In contrast to FeLV, FIV infection produces concentrations of circulating viral antigens that are too low for detection by currently available assays. Culture of peripheral blood mononuclear cells for FIV is a sensitive test for detection of productive viral infection but is not currently available commercially.

PCR is an alternative method for confirming the true FIV status of cats. However, the high sensitivity of PCR may lead to false-positive results if minute amounts of DNA contamination occur during collection, shipping, or processing of samples. Also, FIV has a high intrinsic mutation rate, which has led to the evolution of several distinct genetic subtypes. How well various PCR reagents detect the wide variety of genetically divergent strains present in the environment is unknown, but false-negative results ranging from 10-58% have been reported. Several reference laboratories offer unlicensed FIV-PCR for diagnostic purposes, but virtually nothing is known about their sensitivity, specificity, and diagnostic accuracy.

Fel-O-Vax FIV® is marketed for the prevention of FIV in "at risk" cats, such as those that roam outdoors, reside with FIV-infected cats, or have exposure to untested cats. Vaccine efficacy was 82% in a licensing trial, but performance of the vaccine against the many divergent field strains of FIV has yet to be determined. A transient increase in susceptibility to FIV infection occurs for a few weeks following vaccination with Fel-O-Vax FIV® and certain other vaccines. Thus, cats whose lifestyle puts them at high risk for FIV may experience a temporary, increased risk of infection following vaccination.