The government of Tanzania and some NGOs have been making a lot of efforts to control malaria, but its prevalence is still high in Mtwara Region. Therefore, the research for this dissertation was conducted in Mtwara District in November and December 2010 with the main objective to determine the association between prevalence of malaria, some economic and social factors in rural and urban areas of the district. The specific objectives of the study were to: assess levels of economic and social factors related to frequencies of household members suffering from malaria; assess respondents’ knowledge on symptoms and preventive measures for malaria; estimate the frequency of malaria occurrence among household members; and determine linkages among income levels, education levels of household heads, use of ITNs, use of anti-malaria drugs, distance to health facilities and prevalence of malaria. Data were collected using interview guides and a structured questionnaire. The data were analyzed by using SPSS computer software. Research findings showed that malaria prevalence in urban areas was 18.8% while that in rural areas was 19.2%. However, the difference was not statistically significant at 5% level (p = 0.916). On the linkage between malaria prevalence and some economic and social factors, it was found that malaria prevalence was significantly different in households with higher and those with lower income levels (p = 0.038), and between households located nearby health facilities and those located far (p = 0.006). However, the prevalence wasn’t significantly different between households whose heads had different levels of education (p = 0.069) and those who used ITNs (p = 0.738). Therefore, it is concluded that the economic and social factors mentioned above are significantly associated with malaria prevalence. Based on the above conclusion, it is recommended that the government and other stakeholders should assist the people of Mtwara to eradicate malaria by addressing the above factors with which it is associated.