Background. Comparative effectiveness and systematic reviews require frequent and time-consuming updating. Results of earlier screening should be useful in reducing the effort needed to screen relevant articles. Methods. We collected 16,707 PubMed citation classification decisions from 2 comparative effectiveness reviews: interventions to prevent fractures in low bone density (LBD) and off-label uses of atypical antipsychotic drugs (AAP). We used previously written search strategies to guide extraction of a limited number of explanatory variables pertaining to the intervention, outcome, and study design. We empirically derived statistical models (based on a sparse generalized linear model with convex penalties [GLMnet] and a gradient boosting machine [GBM]) that predicted article relevance. We evaluated model sensitivity, positive predictive value (PPV), and screening workload reductions using 11,003 PubMed citations retrieved for the LBD and AAP updates. Results. GLMnet-based models performed slightly better than GBM-based models. When attempting to maximize sensitivity for all relevant articles, GLMnet-based models achieved high sensitivities (0.99 and 1.0 for AAP and LBD, respectively) while reducing projected screening by 55.4% and 63.2%. The GLMnet-based model yielded sensitivities of 0.921 and 0.905 and PPVs of 0.185 and 0.102 when predicting articles relevant to the AAP and LBD efficacy/effectiveness analyses, respectively (using a threshold of P >= 0.02). GLMnet performed better when identifying adverse effect relevant articles for the AAP review (sensitivity = 0.981) than for the LBD review (0.685). The system currently requires MEDLINE-indexed articles. Conclusions. We evaluated statistical classifiers that used previous classification decisions and explanatory variables derived from MEDLINE indexing terms to predict inclusion decisions. This pilot system reduced workload associated with screening 2 simulated comparative effectiveness review updates by more than 50% with minimal loss of relevant articles.