Desmoplastic tumors show extensive extracellular matrix (ECM) remodeling driven by cancer-associated fibroblasts (CAFs), contributing to tumor progression and treatment resistance. Type XI collagen is elevated in tumor stroma and linked to poor prognosis. This study examined two complementary type XI collagen epitopes: the circulating biomarker PRO-C11 and the matrix-associated epitope CT11a1, including its potential as a stromal drug-delivery target. PRO-C11 was measured in serum from 78 pancreatic ductal adenocarcinoma patients and correlated with clinical benefit rate and overall survival (OS). A CT11a1 ELISA, targeting a C-terminal epitope of mature type XI collagen, was developed and evaluated in serum from 263 solid tumor patients. CT11a1 localization was assessed in pancreatic CAF-derived matrices and human tumor tissue, and a CT11a1-targeting antibody–drug conjugate (ADC) was tested in pancreatic CAF cultures. High baseline PRO-C11 was associated with shorter OS (log-rank p = 0.02). In the landmark analysis, decreasing PRO-C11 correlated with higher clinical benefit rate (52% vs. 20%; p = 0.035) and longer post-landmark OS (log-rank p = 0.01). The CT11a1 ELISA was specific and validated for human serum but showed limited discriminatory ability (AUC 0.52–0.60), while PRO-C11 showed high diagnostic accuracy (AUC 0.89–0.99) and ∼40-fold higher circulating levels. CT11a1 staining localized to CAF-derived ECM and tumor stroma, and CT11a1-ADC reduced CAF viability in vitro. PRO-C11 is a circulating biomarker linked to clinical outcome, while CT11a1 marks matrix-associated type XI collagen and represents a promising stromal drug-delivery target.