Abstract Objective To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people. Design Systematic review and meta-analysis. Data sources PubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies. Study selection Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants. Methods A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed. Results 82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I ² =80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I ² =89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I ² =89%; 0.29, 0.11 to 0.58, I ² =97%), and solid cancers (0.55, 0.46 to 0.65, I ² =78%; 0.44, 0.36 to 0.53, I ² =84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I ² =0%; 0.06, 0.04 to 0.08, I ² =0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I ² =92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I ² =88%; 0.62, 0.54 to 0.70, I ² =90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I ² =92%; 0.77, 0.66 to 0.85, I ² =93%), and solid cancers (0.90, 0.88 to 0.93, I ² =51%; 0.89, 0.86 to 0.91, I ² =49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I ² =0%; 0.97, 0.83 to 1.00, I ² =89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines. Conclusion Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed. Systematic review registration PROSPERO CRD42021272088.