Beta2-microglobulin (β2-M), a marker that is increased in serum during immune activation, was investigated during the course of HIV infection. β2-M rose promptly in the first phase of HIV infection in people who were participating in a longitudinal study where serum samples and lymphocyte subset data were obtained at 6-monthly intervals. A rise in β2-M level in the first seropositive sample was seen in 93% of 50 HIV seroconverters, and those with high (or low) levels of β2-M at the end of year 1 tend to remain high (or low) in the ensuing years. Eighty-three per cent of seroconverters experienced a fall in CD4 T cells in the first year. The magnitude of the CD4 T-cell decline, however, did not correlate with the rise in β2-M in specific individuals in the first year. Nevertheless, 2–3 years after seroconversion, the initially increased β2-M levels did correlate inversely with the (reduced) level of CD4 T cells (P < 0.001). Thus, the pattern of disease reflected by β2-M level is established in the first year of infection and persists through the following 2 years. β2-M levels were found to correlate with rate of CD4 T-cell fall in individuals with established HIV infection. Three groups of HIV-seropositive people with similar CD4 T-cell numbers at the first measurements (about 600–800 × 106/l) but different rates of CD4 T-cell fall over the following 2 years were evaluated by β2-M levels. The group with stable CD4 T-cell numbers showed a significantly lower level of β2-M than the groups with moderately or rapidly declining CD4 T-cell numbers. Increases in β2-M levels during the 2 years of observation were found in people exhibiting a rapid decline in CD4 T cells (about 200 cells/year). The level of β2-M appears to be an indicator of HIV activity and of the rate of CD4 T-cell fall. Serum β2-M level was also found to be a good indicator of AIDS occurrence within 3 years. In a study of 399 men who were seropositive and without AIDS at entry, β2-M and CD4 T cells had about equal predictive power, but the combination of CD4 T cell and β2-M levels provided a more powerful prognostic ability than either alone.