Importance Pituitary adenomas (PAs) present a notable economic burden on healthcare systems due to their management’s reliance on multimodal, often costly interventions. Objective To determine total and relative healthcare costs for PAs at Ontario-based institutions. Design A retrospective, propensity-score-matched cohort analysis. Setting Ontario, Canada, encompassing public healthcare facilities and covering costs over a 6-year study period. Participants Adults diagnosed with PA (n = 1675) between April 1, 2013, and March 31, 2019, compared to a general population cohort and a hospitalized control cohort matched on demographics and health factors. Intervention/Exposures Analysis of healthcare cost components (inpatient, outpatient, and diagnostic services) and cost trajectories postsurgery for PAs. Main Outcome Measures Primary outcome was total annualized healthcare costs for patients with PA relative to the general and hospitalized cohorts. Relative costs were estimated using a negative binomial regression model. Results Of 1675 patients with PA, total annualized costs were $49,992. Highest total costs were associated with inpatient hospitalization ($24,796) and physician services/diagnostic evaluations ($20,075). After propensity score matching, patients with PA had 12.7 times higher costs [95% confidence interval (CI) (10.9, 14.8), P < .0001] during the preadmission/admission period, which remained elevated postoperatively ( P < .05). Total costs did not differ between patients with PA and the hospitalized cohort [RR 0.97, 95% CI (0.92, 1.03); P = .3271] in the preadmission/admission period; however, follow-up costs were 37% lower for patients with PA in the 1st follow-up year [RR 0.63, 95% CI (0.51, 0.77); P < .0001], and up to 50% lower by the 5th year [RR 0.50, 95% CI (0.36, 0.68); P < .0001]. Conclusions This study provided a comprehensive assessment of the economic burden of PAs on the publicly-funded healthcare system. Patients with PA had higher annualized total costs across all observed time periods compared to the general population and lower annualized total costs compared to patients admitted to a surgical ward. Relevance This study highlights the financial impact of PA management on healthcare resources and provides a basis for future research aimed at cost-efficiency improvements in long-term PA care.