Background: Metastatic squamous cell carcinoma (SCCA) of the anal canal is an uncommon malignancy with no standard approach. The reported median overall survival (OS) is 9-12 months (M) following 5-FU + cisplatin (FC)-based therapy. The aim of this study is to evaluate first-line chemotherapy approaches in this patient (pt) population. Methods: A retrospective analysis was conducted of 428 pts with metastatic SCCA of the anal canal identified from the MDACC tumor registry between 1/1/2000 - 5/31/2011. Electronic medical records were reviewed for histology, date of diagnosis and/or recurrence, site of metastasis, type of therapy provided, response rate (RR), progression-free survival (PFS), OS, and lines of salvage therapy. All eligible pts were required to be treatment-naïve for metastatic disease and have radiographic imaging at MDACC. Waiver of informed consent was obtained. Results: 99 pts fulfilled all criteria; 10 were lost to follow-up; 12 did not initiate chemotherapy. 77 pts were evaluable; M: F = 20:57; median age = 55 years (range: 37 - 82); HIV(+) = 5% (4/77); prior chemoXRT with curative intent: 70% (54/77), complete response (CR): 87% (47/54), median time to development of metastatic disease =17M. 29% (22/77) presented with metastatic disease. Sites of disease included distant lymph nodes (41%); liver (45 %); lung (25%); bone (15%); and brain (8%). The median follow up was 37M. 73% (56/77) of patients were treated with platinum-based therapy; 51% (n=39) received FC and 22% (n= 17) received carboplatin + paclitaxel (CP). The median PFS was 6M; FC trended better than CP for PFS (7M vs. 5M, p<0.067). The overall median OS = 29M. 40% (31/77) of pts received neoadjuvant first-line therapy followed by metastasectomy (68%), XRT (26%), or both (6%); resulting in a median OS = 35M. Conclusions: Metastatic SCCA of the anal canal is a malignancy in which 5-FU+cisplatin is a commonly used regimen. Our analysis suggests FC results in improved PFS over CP but is underpowered supporting further analysis. The short median PFS with front-line chemotherapy, and yet longer OS reflects the challenges in treating this patient population and the importance of multidisciplinary management in select cases.