BACKGROUND: Nadofaragene firadenovec (NADO) and oportuzumab monatox (OPOR) are new treatments for bladder cancer unresponsive to BCG therapy. OBJECTIVES: To evaluate the long-term cost-effectiveness of NADO and OPOR compared with a hypothetical bladder cancer treatment (HT) in BCG-unresponsive NMIBC in 2 patient populations: those with 1) carcinoma in situ (CIS) ± high-grade Ta/T1 and 2) high-grade Ta/T1 alone (Ta/T1). Pembrolizumab (PEM) was also evaluated in CIS, and gemcitabine ± docetaxel (GEM/DOC) in both populations. METHODS: A semi-Markov model was developed, employing 3-month cycles over a lifetime horizon, from a healthcare sector perspective. Model inputs were obtained through manufacturer- submitted evidence, systematic literature reviews, and clinical expert opinion. NADO price was based on annual PEM price and OPOR price was a manufacturer provided placeholder price. Primary outcomes, discounted at 3% annually, included total costs (TC), quality-adjusted life years gained (QALY), equal value of life years gained (evLYG), and cost/QALY compared to HT. One-way and probabilistic sensitivity analyses were conducted to evaluate uncertainty. RESULTS: For CIS population: NADO had $308,000 TC, 5.17 QALY, 5.26 evLYG, and $151,000 cost/QALY; OPOR had $310,000 TC, 4.69 QALY, 4.73 evLYG, and $382,000 cost/QALY; PEM had $265,000 TC, 5.04 QALY, 5.12 evLYG, and $114,000 cost/QALY, and GEM/DOC had $172,000 TC, 5.88 QALY, 6.00 evLYG, and dominated HT. For Ta/T1 population: NADO had $302,000 TC, 5.52 QALY, 5.64 evLYG, and $93,000 cost/QALY; OPOR had $302,000 TC, 5.23 QALY, 5.32 evLYG, and $123,000 cost/QALY; and GEM/DOC had $165,000 TC, 5.83 QALY, 5.95 evLYG, and dominated HT. Key uncertainty drivers were probabilities of disease progression to MIBC, NMIBC recurrence beyond 12 months and initial treatment efficacy. CONCLUSIONS: NADO and OPOR may provide bladder-sparing therapeutic alternatives for BCG- unresponsive NMIBC patients. Pricing of these drugs will determine whether they are cost effective at commonly accepted thresholds.