The World Health Organization (WHO) recommends that all human immunodeficiency virus (HIV)–exposed infants begin cotrimoxazole preventive therapy (CPT) between 4 and 6 weeks of age, and continue CPT until at least 6 weeks after cessation of breastfeeding and until HIV infection has been ruled out [1]. CPT is used to avoid often-fatal opportunistic infections among children born to HIV-infected women, and in turn reduces hospital admissions. CPT use among HIV-infected adults and children has been associated with reductions in malaria incidence, as cotrimoxazole has antimalarial activity [2–4]. Similarly, CPT has been associated with reduced incidence of clinical malaria among HIV-exposed but uninfected (HEU) infants, with some suggestion that protective benefits may wane over time [5–7]. As early infant HIV diagnosis services are becoming more widely available in Africa, and as more efficacious drug regimens for the prevention of mother-to-child HIV transmission are being adopted and extended throughout the breastfeeding period, the population of HEU infants is growing. A better understanding of the impact of CPT on malaria among HEU infants is needed. To date, only clinical or symptomatic malaria has been examined in studies of CPT use and malaria incidence. However, clinical malaria represents only a portion of all malaria infections, as many malaria infections are asymptomatic. Although asymptomatic infections are more common in older children, they do occur in infants. We assessed the association between CPT and a composite outcome of clinical or asymptomatic infection. Additionally, we evaluated the association between CPT and both clinical and asymptomatic infections separately. Including asymptomatic infection adds valuable information concerning the routine use of CPT among the growing population of HEU infants, as the role of asymptomatic parasitemia in malaria transmission has garnered increasing attention. Although density of parasitemia and gametocytemia affects transmission efficiency [8], transmission may occur from asymptomatic patients and patients with submicroscopic parasitemia [9]. In addition to assessing the impact of CPT on malaria infection, we also compared characteristics of the asymptomatic infections by CPT status. Specifically, we assessed (1) parasitemia levels; (2) complexity of individual infections, as in high-transmission areas such as Malawi infections are often polyclonal; and (3) frequency of single-nucleotide polymorphisms in dhfr and dhps, the genes associated with resistance to antifolate antimalarials. Because resistance to antifolate antimalarials is common in Africa, understanding how CPT affects parasite characteristics and works in the presence of high levels of antifolate resistance is important.