Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:​1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE:​ 0.46%) for abaloparatide-sMTS and 10.86% (SE:​ 0.48%) for abaloparatide-SC (treatment difference:​ −3.72% [95% confidence interval:​ −5.01%, −2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%;​ abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated;​ however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups.