OBJECTIVE: To study whether absence of prophylaxis is a risk factor for cerebral toxoplasmosis, and to determine the reasons for absence of prophylaxis among AIDS patients diagnosed with Toxoplasma encephalitis (TE). DESIGN: Retrospective chart review and matched case-control study. PATIENTS: Patients (104 first episodes and 26 relapses of TE) were registered in the Swiss HIV Cohort Study from three centres from July 1992 to December 1994; 91 matched controls were included for 52 patients with a first episode, and 17 matched controls for 17 patients with relapse of TE. RESULTS: Prophylaxis was prescribed to 17 patients (16%) with a first episode and 19 patients (73%) with a relapse of TE. Reasons for the absence of prophylaxis included patient refusal (25%), non-proposal by physicians (17%), and drug intolerance (17%). Reduced absorption due to non-compliance, diarrhoea or vomiting was identified among 12 patients with a first episode and 14 patients with a relapse of TE. Absence of prescription of prophylaxis was associated with a 10-fold increased risk of a first episode of TE (odds ratio, 9.8; 95% confidence interval, 2.7-35.4) in the matched case-control study. CONCLUSIONS: TE continues to occur among patients not receiving prophylaxis. At least one-half of the cases may be prevented with better motivation of physicians and increased compliance of patients.