ObjectiveTo systematically review the evidence on the effect of cotrimoxazole (CTX) on malaria in HIV-positive individuals on antiretroviral therapy (ART).MethodsWeb of Science, PubMed and MEDLINE, EMBASE, Global Health and Cochrane Library databases were searched using terms for malaria, HIV and CTX. Studies meeting the inclusion criteria were reviewed and assessed for bias and confounding.ResultsSix studies (in Uganda, Kenya, Malawi, Zambia and Zimbabwe) had relevant data on the effect of CTX on malaria in patients on ART: four were observational cohort studies (OCS) and two were randomised controlled trials (RCTs); two were in children and one in women only. Samples sizes ranged from 265 to 2200 patients. Four studies compared patients on ART and CTX with patients on ART alone; 2 (RCTs) found a significant increase in smear-positive malaria on ART alone: (IRR 32.5 CI=8.6-275.0 and HR 2.2 CI=1.5-3.3) and 2 (OCS) reported fewer parasitaemia episodes on CTX and ART (OR 0.85 CI=0.65-1.11 and 3.6% vs. 2.4% of samples P=0.14). One OCS found a 76% (95% CI=63-84%) vs. 83% (95% CI=74-89%) reduction in malaria incidence in children on CTX and ART vs. on CTX only, when both were compared with HIV-negative children. The other reported a 64% reduction in malaria incidence after adding ART to CTX (RR=0.36, 95% CI=0.18-0.74). The 2 RCTs were unblinded. Only one study reported adherence to CTX and ART, and only two controlled for baseline CD4 count.ConclusionFew studies have investigated the effect of CTX on malaria in patients on ART. Their findings suggest that CTX is protective against malaria even among patients on ART.