Objective To assess the cognitive effectiveness and safety of tau-targeting drugs for Alzheimer's disease (AD) Methods The MEDLINE, Embase, Cochrane Library, PsycINFO, , and WHO International Clinical Trials Registry Platform databases were searched from inception to 22 November 2021. A systematic review and meta-analysis of randomized controlled trials were performed Results Thirty-four randomized controlled trials comprising 5549 participants, of which fifteen (51.7%) had a low risk of bias, were included. The meta-analysis showed no differences in the cognitive subscale of the AD: Assessment Scale (ADAS-Cog) between anti-tau drugs and placebo (mean difference [MD]: -0.77, 95% CI: -1.64 to 0.10; minimal important difference 3.1-3.8 points, moderate certainty evidence). For ADAS-Cog, the results subgroup analysis suggested a statistical effect of tau posttranslational modifications on drug inhibition (MD: -0.80, 95% CI: -1.43 to -0.17), which was not seen with tau aggregation inhibitors or immunotherapy (interaction p = 0.24). A total of 11.0%, 5.2%, and 4.8% of drugs inhibiting tau aggregation, immunotherapy, and drugs targeting posttranslational modifications, respectively, had a reduced risk of dropouts due to adverse events (AEs). Discussion Current evidence suggests that anti-tau drugs are unlikely to have an important impact on slowing cognitive impairment. Although the subgroup analysis suggested that inhibition of tau posttranslational modifications is statistically effective and generally safer because of reduced dropouts due to AEs, the analysis has limited credibility. Additional large-scale and well-designed randomized and placebo-controlled trials will be necessary to explore the benefit of a certain type of anti-tau drug for AD.