Toxoplasmic encephalitis (TE) is the most important opportunistic infection of the central nervous system in patients infected with human immunodeficiency virus (HIV)-1. This study evaluated the effect of highly active anti-retroviral therapy (HAART) and Toxoplasma gondii-specific immune responses on the occurrence of TE. The clinical characteristics of all patients diagnosed with TE in two centres since 1990 (n = 140) were analysed. Patients were grouped according to the date of diagnosis (period 1, 1990-1993; period 2, 1994-1996; period 3, 1997 onwards). Immune responses to T. gondii were evaluated in a subgroup (n = 12) by interferon (IFN)-gamma-specific ELISPOT tests. There were marked differences in the estimated Kaplan-Meier overall survival (OS), with a 1-year OS (5-year OS) of 41% (7%) in period 1, 56% (29%) in period 2, and 90% (78%) in period 3 (p <0.0001). In period 3, TE was found to be the first AIDS-defining illness more frequently than in earlier periods (74% vs. 38%, p 0.0002). Persistent neurological deficits caused by TE were present in 37% of the patients. Patients with an acute episode of TE or a TE relapse had significantly lower responses in the T. gondii-specific ELISPOT than patients who discontinued maintenance therapy and were relapse-free (p 0.0044). Survival of HIV patients with TE has improved markedly since the introduction of HAART, but persistent neurological deficits are often present in surviving patients. While preventive therapy remains essential, evaluation of T. gondii-specific immune responses may be an important step in improving estimates of the individual risk of TE and TE relapses.