Background The association of family-witnessed cardiopulmonary resuscitation (CPR) and subsequent advance directives in the medical intensive care unit is unknown. Objective To compare clinical outcomes, including subsequent limitations on care, of family-witnessed vs family-unwitnessed CPR in the inpatient setting. Methods Analysis of demographics and outcomes pertaining to family presence in a retrospective cohort of consecutive patients receiving first CPR in the medical intensive care unit of a tertiary academic medical center. Results In 5 years, 323 patients underwent attempted CPR, of which 49 attempts (15.2%) were witnessed by family. In patients with return of spontaneous circulation, 40.9% of those whose first CPR was witnessed by family later had a do not attempt resuscitation order, which did not differ from patients whose first CPR was unwitnessed by family (31.8%). Family-witnessed CPR in the unit was associated with significantly lower rates of return of spontaneous circulation (44.9%) than was family-unwitnessed CPR (62.0%; P = .02). Of all patients with a first CPR, 42 (13.0%) survived to hospital discharge. Only 1 patient with return of spontaneous circulation after first family-witnessed CPR survived to hospital discharge. In-hospital mortality for all patients requiring subsequent CPR was 97.1%. Conclusions For unclear reasons, family-witnessed CPR in the medical intensive care unit is associated with a similar rate of subsequent CPR efforts and lower rates of return of spontaneous circulation and survival to hospital discharge.