Abstract Background: Guideline-concordant local therapy options for early breast cancer include lumpectomy plus whole breast irradiation (lump+WBI), lumpectomy plus brachytherapy (lump+brachy), mastectomy without reconstruction or radiation (mast alone), mastectomy with reconstruction without radiation (mast+recon), and, in older women, lumpectomy without radiation (lump alone). Little is known regarding the comparative complication and economic burden of these options in the general population. Methods: We used the MarketScan database which includes younger women with private insurance and the SEER-Medicare database which includes older women with Medicare. Women were included if they had early stage disease (T1/2 N0/1 M0) diagnosed in 2000-2011, no prior cancer, and complete insurance coverage from 12 months prior through 24 months after diagnosis. A complication from local therapy was defined as a diagnosis or procedure code for any of the following within 24 months of diagnosis: wound complication, local infection, seroma/hematoma, fat necrosis, breast pain, pneumonitis, rib fracture, and implant removal. Total costs and complication-related costs within 24 months of diagnosis were calculated from a payer's perspective and are reported in 2014 dollars. Logistic regression compared complications by local therapy and generalized linear regression (log link function, gamma distribution) compared complication-related and total costs by local therapy; all models adjusted for relevant covariables. Results: We selected 44,344 patients from the MarketScan cohort, median age of 53, and 50,562 patients from the SEER-Medicare cohort, median age of 75. For the MarketScan cohort, risk of complications varied as follows: 29% risk in patients treated with lump+WBI (referent), 44% with lump+brachy (adjusted odds ratio [AOR]=2.00;P<.001), 25% with mast alone (AOR=0.85;P<.001), and 54% with mast+recon (AOR=2.89;P<.001). For the SEER-Medicare cohort, risk of complications varied as follows: 37% with lump+WBI (referent), 52% with lump+brachy (AOR=1.91;P<.001), 37% with mast alone (AOR=0.97;P=.17), 65% with mast+recon (AOR=3.17; P<.001), and 30% with lump alone (AOR=0.81; P<.001). Compared to lump+WBI, mean adjusted complication-related cost was $8,085 higher per patient with mast+recon in the MarketScan cohort and $3,711 higher per patient with mast+recon in the SEER-Medicare cohort. In contrast, complication-related costs were similar (+/- $750) for all other local therapy options relative to lump+WBI in both cohorts. For total cost, mast+recon was the most expensive local therapy in the MarketScan cohort, with mean adjusted total cost of $77,321, which was $15,181 more expensive than lump+WBI. In the SEER-Medicare cohort, lump+brachy was the most expensive option ($39,534), followed by mast+recon ($35,269), lump+WBI ($32,562), mast alone ($26,401), and lump alone ($24,455). Conclusion: Mast+recon results in the highest complication rate and complication-related cost in both younger women and older women with early breast cancer. These findings are relevant to defining which local therapies offer the highest value to patients, payers, and society, and are relevant to patients when evaluating their local therapy options. Citation Format: Smith BD, Jiang J, Shih Y-CT, Giordano SH, Huo J, Jagsi R, Caudle AS, Hunt KK, Shaitelman SF, Buchholz TA, Shirvani SM. Complication and economic burden of local therapy options for early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S3-07.