OBJECTIVES Hospital-acquired infections (HAIs) develop rapidly after brief and transient exposures, and ecological exposures are central to their etiology. However, many studies of HAIs risk do not correctly account for the timing of outcomes relative to exposures, and they ignore ecological factors. We aimed to describe statistical practice in the most cited HAI literature as it relates to these issues, and to demonstrate how to implement models that can be used to account for them. METHODS We conducted a literature search to identify 8 frequently cited articles having primary outcomes that were incident HAIs, were based on individual-level data, and used multivariate statistical methods. Next, using an inpatient cohort of incident Clostridium difficile infection (CDI), we compared 3 valid strategies for assessing risk factors for incident infection: a cohort study with time-fixed exposures, a cohort study with time-varying exposures, and a case-control study with time-varying exposures. RESULTS Of the 8 studies identified in the literature scan, 3 did not adjust for time-at-risk, 6 did not assess the timing of exposures in a time-window prior to outcome ascertainment, 6 did not include ecological covariates, and 6 did not account for the clustering of outcomes in time and space. Our 3 modeling strategies yielded similar risk-factor estimates for CDI risk. CONCLUSIONS Several common statistical methods can be used to augment standard regression methods to improve the identification of HAI risk factors. Infect.