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Aims: Previous trials on the effectiveness of genotype‐guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta‐analysis of randomized trials comparing genotype‐guided to conventional dosing strategies. Methods: PubMed and the Cochrane Library were searched up to 23 October 2017. Results: A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype‐guided dosing (mean age 63.3 ± 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1 years; 46% male) groups (mean follow‐up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype‐guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype‐guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2: 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. Conclusions: Genotype‐guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident. [ABSTRACT FROM AUTHOR]