Background Scant data exists to guide the work-up for fever in hospitalized patients, and little is known about what diagnostic tests medicine residents order for such patients. We sought to analyze how cross-covering medicine residents address fever and how sign-out systems affect their response. Methods We conducted a prospective cohort study to evaluate febrile episodes that residents responded to overnight. Primary outcomes included diagnostic tests ordered, if an in-person evaluation occurred, and the effect of sign-out instructions that advised a "full fever work-up" (FFWU). Results Investigators reviewed 253 fevers in 155 patients; sign-out instructions were available for 204 fevers. Residents evaluated the patient in person in 29 (11%) episodes. The most common tests ordered were: blood cultures (48%), urinalysis (UA) with reflex culture (34%), and chest X-ray (30%). If the sign-out advised an FFWU, residents were more likely to order blood cultures [odds ratio (OR) 14.75, 95% confidence interval (CI) 7.52-28.90], UA with reflex culture (OR 12.07, 95% CI 5.56-23.23), chest X-ray (OR 16.55, 95% CI 7.03-39.94), lactate (OR 3.33, 95% CI 1.47-7.55), and complete blood count (CBC) (OR 3.16, 95% CI 1.17-8.51). In a multivariable regression, predictors of the number of tests ordered included hospital location, resident training level, timing of previous blood culture, in-person evaluation, escalation to a higher level of care, and sign-out instructions. Conclusions Sign-out instructions and a few patient factors significantly impacted cross-cover resident diagnostic test ordering for overnight fevers. This practice can be targeted in resident education to improve diagnostic reasoning and stewardship.