Drug-resistant P.falciparum malaria is an increasing concern in sub-Saharan Africa (SSA), where previously effective monotherapy treatments were replaced by artemisinin combination therapies (ACT) because of resistance. ACTs typically have a good safety profile and high efficacy responses (>95%). Resistance to ACTs has been documented in Asia, but has not been observed in SSA. However, there are now signs artemisinin-resistance may be spreading to the African continent. An indication of artemisinin resistance is delayed parasite clearance time (PCT), defined as a slope half-life >5 hours (time to clear 50% of parasites). Artemisinin resistance may also cause ACT treatment failure (recrudescence). It is not clear though if delayed PCT or recrudescence is consistently explained by parasite factors such as resistance or host factors such as immunity. Exploring the determinants of both delayed PCT and recrudescence is the aim of this dissertation. Data from a large multi-center clinical trial conducted in 2006-7 when ACTs were first introduced in SSA were utilized for these analyses (n=1372). Candidate variables included: baseline parasitemia, sex, treatment, and surrogate factors for immunity (age, estimated endemicity, seasonality, previous malaria episodes, and geographic location). Logistic regression was used to assess significant factors associated with each outcome. In Aim 1, we found 24 cases with delayed PCT. Since the study occurred prior to the widespread introduction of ACTs in Africa, our data suggests that resistant parasite strains pre-existed the introduction of ACTs. Site (p<0.001) and baseline parasitemia (p<0.001) were significantly associated with delayed PCT. In Aim 2, slope half-life (p<0.001), treatment (p=0.004), seasonality (p=0.008), and endemicity (p=0.018) were significant factors in explaining recrudescence, with age (p=0.076) and sex (p=0.106) also having marginal contributions. In summary, our findings suggest that delayed PCT pre-dated the widespread use of artemisinin in Africa and that recrudescence may be related to environmental, host and parasite factors.