People who are homeless have a higher burden of illness and higher rates of hospital admission and readmission compared to the general population. Identifying the factors associated with hospital readmission could help healthcare providers and policymakers improve post-discharge care for homeless patients. To identify factors associated with hospital readmission within 90 days of discharge from a general internal medicine unit among patients experiencing homelessness. This prospective observational study was conducted at an urban academic teaching hospital in Toronto, Canada. Interviewer-administered questionnaires and chart reviews were completed to assess medical, social, processes of care, and hospitalization data. Multivariable logistic regression with backward selection was used to identify factors associated with a subsequent readmission and estimate odds ratios and 95% confidence intervals. Adults (N = 129) who were admitted to the general internal medicine service between November 2017 and November 2018 and who were homeless at the time of admission. Unplanned all-cause readmission to the study hospital within 90 days of discharge. Thirty-five of 129 participants (27.1%) were readmitted within 90 days of discharge. Factors associated with lower odds of readmission included having an active case manager (adjusted odds ratios [aOR]: 0.31, 95% CI, 0.13-0.76), having informal support such as friends and family (aOR: 0.25, 95% CI, 0.08-0.78), and sending a copy of the patient's discharge plan to a primary care physician who had cared for the patient within the last year (aOR: 0.44, 95% CI, 0.17-1.16). A higher number of medications prescribed at discharge was associated with higher odds of readmission (aOR: 1.12, 95% CI, 1.02-1.23). Interventions to reduce hospital readmission for people who are homeless should evaluate tailored discharge planning and dedicated resources to support implementation of these plans in the community.