The highlands of Ethiopia, situated between 1,500 and 2,500 m above sea level, experienced severe malaria epidemics. Despite the intensive control attempts, underway since 2005 and followed by an initial decline, the disease remained a major public health concern. The aim of this study was to identify malaria risk factors in highland-fringe south-central Ethiopia. This study was conducted in six rural kebeles of Butajira area located 130 km south of Addis Ababa, which are part of demographic surveillance site in Meskan and Mareko Districts, Ethiopia. Using a multistage sampling technique 750 households was sampled to obtain the 3,398 people, the estimated sample size for this study. Six repeated cross-sectional surveys were conducted from October 2008 to June 2010. Multilevel, mixed-effects logistic regression models fitted to Plasmodium infection status (positive or negative) and six variables. Both fixed- and random-effects differences in malaria infection were estimated using median odds ratio and interval odds ratio 80%. The odds ratios and 95% confidence intervals were used to estimate the strength of association. Overall, 19,207 individuals were sampled in six surveys (median and inter-quartile range value three). Six of the five variables had about two-fold to eight-fold increase in prevalence of malaria. Furthermore, among these variables, October-November survey seasons of both during 2008 and 2009 were strongly associated with increased prevalence of malaria infection. Children aged below five years (adjusted OR= 3.62) and children aged five to nine years (adj. OR= 3.39), low altitude (adj. OR= 5.22), mid-level altitude (adj. OR= 3.80), houses with holes (adj. OR= 1.59), survey seasons such as October-November 2008 (adj. OR= 7.84), January-February 2009 (adj. OR= 2.33), June-July 2009 (adj. OR=3.83), October-November 2009 (adj. OR= 7.71), and January-February 2010 (adj. OR= 3.05) were associated with increased malaria infection. The estimates of cluster variances revealed differences in malaria infection. The village-level intercept variance for the individual-level predictor (0.71 [95% CI: 0.28-1.82]; SE=0.34) and final (0.034, [95% CI: 0.002-0.615]; SE=0.05) were lower than that of empty (0.80, [95% CI: 0.32-2.01]; SE=0.21). Malaria control efforts in highland fringes must prioritize children below ten years in designing transmission reduction of malaria elimination strategy.