The Bioko Island Malaria Control Project (BIMCP) has carried out intensive interventions since early 2004 to reduce malaria transmission through indoor residual spraying (IRS) and case management. Annual parasite prevalence surveys have been carried out to monitor the effectiveness of the program. Significant overall reductions in prevalence of infection have been observed, with 42% fewer infections occurring in 2006 compared with baseline. Nevertheless, there is evidence of considerable heterogeneity in impact of the intervention. Prevalence of infection was significantly associated with spray status of the child's house, spray coverage with effective insecticide of the neighborhood of the house, bed net use, and time elapsed since last spray. Careful scheduling of spray coverage is therefore essential to maximize the effectiveness of IRS and to ensure consistent reductions in parasite prevalence. This can only be achieved if comprehensive monitoring systems are in place for both the management and evaluation of the intervention.