Treatment modifications are necessary for addressing issues related to efficacy and tolerance of first-line monotherapy, but they increase the economic burden on patients and their health plans. Understanding the differences in costs between alternative treatment modification strategies, if any, can serve as a guideline for clinical decision making and for designing cost-containment strategies. To compare the health care utilization costs between (a) addition (i.e., use of free-pill combinations [FPCs] or fixed-dose combinations [FDCs]) and uptitration as alternatives for addressing efficacy issues and (b) switching and downtitration as alternatives for addressing tolerance issues with first-line antihypertensive monotherapy. This is a retrospective cohort study that used the 2008-2012 BlueCross BlueShield of Texas claims database. Patients who had a treatment modification within 12 months of initiating antihypertensive monotherapy were identified. All-cause and disease-related health care utilization costs and drug costs were estimated from the BlueCross BlueShield health plan's perspective over a 12-month period, starting from the date of treatment modification. Propensity score-adjusted generalized linear models were used to compare costs between alternative treatment modification strategies. We identified 5,998 patients who met study criteria and had a modification of treatment: FPC (n = 1,395), FDC (n = 1,207), uptitration (n = 1,659), switching (n = 1,282), and downtitration (n = 455). All-cause and disease-related health services utilization costs were estimated for 12 months following treatment modification. Mean annual drug utilization costs were highest for the FDC strategy. All-cause inpatient and outpatient services utilization costs were significantly different between strategies used for addressing issues of tolerance and efficacy, respectively. Disease-related inpatient services utilization costs were lower for the FDC strategy compared with the uptitration strategy. However, disease-related inpatient services utilization costs were not significantly different for the downtitration strategy compared with the switch strategy. Health care costs following treatment modifications vary by type of strategy. The high costs of FDCs may be offset by the reduction of inpatient services utilization costs. Careful consideration should be given to the differences in costs between alternative strategies. No outside funding supported this study. The dataset used in this study was created for dissertational research on the patterns and outcomes of treatment modification in hypertensive patients. Data and database support were provided by University of Texas School of Public Health/BlueCross BlueShield of Texas research program in payment systems and policy. Sonawane Deshmukh was an employee of Anthem BlueCross BlueShield from August 2015 to August 2016. Hansen has received consulting funds from Daichii Sankyo and has provided expert testimony for Allergan and Boehringer Ingelheim. All other authors have no known conflicts of interest. Study concept and design were contributed by Sonawane Deshmukh, Garza, Wright, and Hansen. Sonawane Deshmukh and Ganduglia Cazaban collected the data, and data interpretation was performed by Sonawane Deshmukh, Qian, Wright, and Zeng. The manuscript was written primarily by Sonawane Deshmukh, along with Qian and Garza, and revised by Sonawane Deshmukh, Qian, Ganduglia Cazaban, and Hansen.