OBJECTIVES: To describe the characteristics of individuals undergoing toxicology testing at delivery for a sole indication of cannabis use and to evaluate the rate of unexpected positive toxicology testing results among this cohort. METHODS: This retrospective cohort study included dyads with a maternal history of cannabis use who underwent peripartum toxicology testing between 2016 and 2020 at 5 birthing hospitals in Massachusetts. We collected information on maternal demographic characteristics and toxicology test results and reviewed records of dyads with unexpected positive results to identify additional social risk factors and clinical outcomes. RESULTS: Of 60 608 live births reviewed, 1924 dyads underwent toxicology testing, including 614 (31.9%) for a sole indication of cannabis use. Significantly greater percentages of patients in the cannabis cohort were <25 years old (32.4% vs 6.1% of the birthing population, P <.001), non-Hispanic Black (32.4% vs 8.1%, P < .001), Hispanic or Latino (30.5% vs 15.5%), American Indian/Alaskan (0.7% vs 0.1%), and publicly insured (39.9% vs 15.6%, P <.001). Eight of the 614 dyads (1.3%) had an unexpected positive toxicology test result, including 2 (0.3%) unexpectedly positive for opioids. Seven dyads (1.1%) had false positive test results for unexpected substances. Only 1 test result changed clinical management; a urine test positive for opioids prompted monitoring (but not medication) for neonatal opioid withdrawal syndrome. CONCLUSIONS: Toxicology testing of patients for a sole indication of cannabis use, without other risk factors, may be of limited utility in elucidating other substance use and may exacerbate existing disparities in perinatal outcomes.