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Phlebolymphedema (chronic venous insufficiency-related lymphedema) is a common and costly condition. Nevertheless, there is a dearth of evidence comparing phlebolymphedema therapeutic interventions. This study sought to examine the medical resource utilization and phlebolymphedema-related cost associated with Flexitouch (FLX; Tactile Medical, Minneapolis, Minn) advanced pneumatic compression devices (APCDs) relative to conservative therapy (CONS) alone, simple pneumatic compression devices (SPCDs), and other APCDs in a representative U.S. population of phlebolymphedema patients.This was a longitudinal matched case-control analysis of deidentified private insurance claims. The study used administrative claims data from Blue Health Intelligence for the complete years 2012 through 2016. Patients were continuously enrolled for at least 18 months, diagnosed with phlebolymphedema, and received at least one claim for CONS either alone or in addition to pneumatic compression (SPCDs or APCDs). The main outcomes included direct phlebolymphedema- and sequelae-related medical resource utilization and costs.After case matching, the study included 86 patients on CONS (87 on FLX), 34 on SPCDs (23 on FLX), and 69 on other APCDs (67 on FLX). Compared with CONS, FLX was associated with 69% lower per patient per year total phlebolymphedema- and sequelae-related costs net of any pneumatic compression device-related costs ($3839 vs $12,253; P = .001). This was driven by 59% fewer mean annual hospitalizations (0.13 vs 0.32; P .001) corresponding to 82% lower inpatient costs and 55% lower outpatient hospital costs. FLX was also associated with 52% lower outpatient physical therapy and occupational therapy costs and 56% lower other outpatient-related costs. Compared with SPCDs, FLX was associated with 85% lower total costs ($1153 vs $7449; P = .008) driven by 93% lower inpatient costs ($297 vs $4215; P = .002), 84% lower outpatient hospital costs ($368 vs $2347; P = .020), and 85% lower other outpatient-related costs ($353 vs $2313; P = .023). Compared with APCDs, FLX was associated with 53% lower total costs ($3973 vs $8436; P = .032) because of lower outpatient costs and lower rates of cellulitis (22.4% vs 44.9% of patients; P = .02).This analysis indicates significant benefits attributable to FLX compared with alternative compression therapies that can help reduce the notable economic burden of phlebolymphedema.