Objectives. To examine how operational rules are established and enforced at an unsanctioned safe consumption site (SCS) operating in the United States. Methods. We conducted 44 qualitative interviews with people who use drugs, staff members, and volunteers at an unsanctioned SCS and analyzed them using an inductive thematic approach. Results. Rule-making processes were largely driven by concerns raised by service users rather than driven by external pressures, and iterated rapidly in response to changing needs. The unsanctioned nature of the site produced an environment where bottom-up rule-making was critical to generating a shared sense of ownership of the site and where enforcement was necessarily fluid. Conclusions. Removing external restrictions on operational rules for SCSs results in a flexible set of rules that are highly responsive to the social and public health needs of people who use drugs. Legislation and regulations of SCSs should aim to place as few hard limits on operating conditions as possible to maximize involvement of and responsiveness to people who use drugs. (Am J Public Health. 2022;112(S2):S166-S172. https://doi.org/10.2105/AJPH.2022.306714).