Sera from cats with naturally acquired and experimentally induced feline immunodeficiency virus (FIV) infections were tested by immunoblot analysis, radioimmunoprecipitation assay (RIPA), and a complex trapping/blocking ELISA. In sequentially obtained samples from experimentally inoculated cats, antibodies against the envelope protein gp120 and the core protein p15 were the first to appear, as indicated by results of RIPA, using lysates of FIV-infected lymphocytes. Antibodies could be detected as early as 2 weeks after infection, followed by a response against p24, p43, and p50. By immunoblot analysis, p24 and p15 were the first proteins detectable between postinoculation weeks 3 and 5; an anti-envelope response was never found by use of this assay, but was found by RIPA. Using the latter test, most sera of naturally infected cats were found to recognize the major core protein p24 in addition to 1 or more minor core proteins. All 40 sera tested precipitated the envelope protein; 3 reacted exclusively with it. A complex trapping/blocking ELISA was developed to quantitate the anti-p24 response. Sera from healthy FIV-infected cats were shown to have higher anti-p24 titer than did those from diseased cats.