ImportanceLittle is known about the safety of midline catheters vs peripherally inserted central catheters (PICCs) for outpatient parenteral antimicrobial therapy (OPAT).ObjectiveTo compare outcomes from midline catheters vs PICCs for OPAT.Design, Setting, and ParticipantsThis retrospective cohort study included patients who received antimicrobial therapy through a midline catheter or PICC between January 2017 and November 2023 across 69 Michigan hospitals. Because peripherally compatible OPAT was the indication of interest, vancomycin therapy was excluded. Data were analyzed from April to June 2024.ExposuresInsertion of a midline catheter or PICC for OPAT following hospitalization.Main Outcomes and MeasuresThe primary outcome was major device complications (ie, catheter-related bloodstream infection or catheter-related venous thromboembolism). Secondary outcomes included minor device complications (eg, catheter dislodgement, occlusion, tip migration, infiltration, superficial thrombophlebitis, or exit site concerns) and device failure, defined as catheter removal following device complication. Cox proportional hazards regression models were fit to device type and outcomes, adjusting for patient and device confounders and device dwell.ResultsOf 2824 included patients, 1487 (53.5%) were male, and the median (IQR) age was 66.8 (55.9-77.1) years. Of 2824 devices placed for OPAT, 1999 (70.8%) were midline catheters and 825 (29.2%) were PICCs. The median (IQR) dwell time was 12 (8-17) days for midline catheters and 19 (12-27) days for PICCs (P < .001). A major device complication occurred in 44 patients (1.6%) overall, including 16 (0.8%) with midline catheters and 28 (3.4%) with PICCs (P < .001). OPAT delivered via midline catheters was associated with a lower risk of major complications vs PICCs (adjusted hazard ratio [aHR], 0.46; 95% CI, 0.23-0.91). Risks of minor complications and device failure were similar across device types (minor complications: 206 of 1999 [10.3%] vs 114 of 825 [13.8%]; aHR, 1.07; 95% CI, 0.83-1.38; device failure: 191 of 1999 [9.6%] vs 100 of 825 [12.1%]; aHR, 1.26; 95% CI, 0.96-1.65). For device dwell of 14 or fewer days, midline catheters were associated with a lower risk of major complications (12 of 1324 [0.9%] vs 16 of 304 [5.3%]; aHR, 0.29; 95% CI, 0.12-0.68) and similar risk of failure (151 of 1324 [11.4%] vs 52 of 304 [17.1%]; aHR, 0.79; 95% CI, 0.56-1.12) vs PICCs. For dwell longer than 14 days, no significant difference in rates of major complications (4 of 675 [0.6%] vs 12 of 521 [2.3%]; aHR, 0.42; 95% CI, 0.13-1.40) or device failure (40 of 675 [5.9%] vs 48 of 521 [9.2%]; aHR, 1.02; 95% CI, 0.64-1.61) were observed.Conclusions and RelevanceIn this study, midline catheters appeared to be safe alternatives to PICCs for OPAT, particularly if infusions were planned for 14 or fewer days.