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Toxoplasmic encephalitis (TE) is an opportunistic infection of people living with HIV or other causes of immunosuppression. For decades, the standard of care has been combination therapy with pyrimethamine and sulfadiazine (P-S) or pyrimethamine and clindamycin (P-C). However, a substantial price increase has starkly limited access to pyrimethamine. Consequently, some centers have transitioned to trimethoprim-sulfamethoxazole (TMP-SMX), an inexpensive alternative treatment. We aimed to systematically review the evidence to compare the efficacy and safety of pyrimethamine-containing therapies versus TMP-SMX.We searched for and included randomized controlled trials (RCT) and observational studies of TE treatments, regardless of HIV status. Data for each therapy were pooled by meta-analysis to assess the proportions of patients experiencing clinical and radiologic responses to treatment, all-cause mortality, and discontinuation due to toxicity. Sensitivity analyses limited to RCTs directly compared therapies.We identified 6 RCTs/dose-escalation studies and 26 single-arm/observational studies. Pooled proportions of clinical and radiologic response or mortality or were not significantly different between TMP-SMX and pyrimethamine-containing regimens (P > 0.05). Treatment discontinuation due to toxicity was significantly lower in TMP-SMX (7.3%, 95%CI 4.7-11.4, I2 = 0.0%) versus P-S (30.5%, 95%CI 27.1-34.2, I2 = 0.0%, P < 0.01) or P-C (13.7%, 95%CI 9.8-18.8, I2 = 32.0%, P = 0.031). These results were consistent in analyses restricted to RCT data.Identified studies only included persons living with HIV and most predated modern antiretroviral treatment.TMP-SMX appears to be as effective and safer than the pyrimethamine-containing regimens for TE. These findings support modern RCTs comparing TMP-SMX to P-S or P-C and a revisiting of the guidelines.