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To investigate the incidence and risk factors of immune reconstitution inflammatory syndrome (IRIS) associated with toxoplasmic encephalitis (TE) in patients starting combination antiretroviral therapy (cART).A historical multicenter cohort study.We included all HIV-infected patients diagnosed with toxoplasmic encephalitis in six Dutch hospitals between 1996 and 2016. Diagnosis of TE–IRIS was made using predefined IRIS criteria. We distinguished paradoxical TE–IRIS (worsening of underlying treated infection) from unmasking TE–IRIS (unmasking of subclinical infection after start of cART). We compared CD4+ cell count, plasma viral load and timing of cART initiation between patients with and without paradoxical TE–IRIS.A total of 211 toxoplasmic encephalitis cases were included. Among 143 cases at risk for paradoxical TE–IRIS, we identified five cases of paradoxical TE–IRIS (3.5%). In six other cases, we could not differentiate paradoxical TE–IRIS from recurrence of disease due to inadequate secondary Toxoplasma prophylaxis. There was no difference in time between start of toxoplasmic encephalitis treatment and cART initiation for patients who did or did not develop paradoxical TE–IRIS (P = 0.50). Within the group of 2228 patients who started cART while having a CD4+ cell count below 200 × 106 cells/l and receiving adequate primary prophylaxis, we identified eight cases of unmasking TE–IRIS (0.36%). Unmasking TE–IRIS could not be differentiated from a newly occurring toxoplasmic encephalitis in six other patients, as they were not receiving adequate primary prophylaxis against Toxoplasma.Unmasking TE–IRIS was rare in this cohort, whereas paradoxical TE–IRIS did occur more often. We found no relationship between the timing of cART initiation and the occurrence of paradoxical TE–IRIS.