To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADC) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane-permeable antimitotic agent. Site-selective 177Lu-labeled ADCs [anti-trophoblast cell-surface antigen 2 (TROP2) 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs], a 177Lu-labeled homogeneous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumors. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2 ADC and anti-TROP2 homogeneous RIC showed significantly improved radioactivity accumulation in the TROP2-expressing JIMT-1 tumor (P < 0.01 at 72 hours). In the therapeutic study, 177Lu-DTPA TROP2 ADC (5 MBq; 1.5 mg/kg) suppressed tumor growth significantly more than did the anti-TROP2 homogeneous RIC (5 MBq, P = 0.0068). Anti-HER2 177Lu-DO3A ADC (5 MBq; 3.0 mg/kg) demonstrated greater in vivo treatment efficacy over monomethyl auristatin E DAR 2 HER2 ADC (3.0 mg/kg) monotherapy, anti-HER2 homogeneous RIC (5 MBq) monotherapy, and the combination of monomethyl auristatin E DAR 2 HER2 ADC and anti-HER2 homogeneous RIC at matched payload and radioactivity doses in a refractory breast tumor model displaying heterogeneous HER2 expression. These results suggest that site-selectively 177Lu-labeled ADCs are effective in treating refractory tumors, including those with heterogeneous antigen expression, and warrant further exploration as a promising single-agent, dual-mechanistic treatment modality for solid tumors.