Background: The combination of cisplatin and 5-fluorouracil (5-FU) is a standard chemotherapy regimen for advanced anal squamous cell cancer (AC) and is associated with significant toxicity. We examined the efficacy of a modified schedule, FOLFCIS, and performed an integrated clinical and genomic analysis of advanced AC. Methods: We reviewed all patients with metastatic or recurrent locally advanced AC treated with first line FOLFCIS chemotherapy at Memorial Sloan Kettering Cancer Center (MSK) between January 2007 and July 2017. FOLFCIS, which is essentially FOLFOX with cisplatin substituted for oxaliplatin, consisted of cisplatin 40 mg/m² day 1, leucovorin 400 mg/m² day 1, 5-FU 400 mg/m² day 1, 5-FU 1000 mg/m²/d days 1 and 2 in a 14-day cycle. Forty-one advanced AC patients underwent targeted next generation tumor sequencing of > 300 genes (MSK-IMPACT), including 23 of the patients treated with FOLFCIS. Results: Fifty-three AC patients (48 metastatic; 5 unresectable, locally advanced) received first line FOLFCIS during this period; all were platinum naive. Median age was 59 years, and 32% had metastatic disease at diagnosis. Thirteen patients (25%) received multimodal treatment for metastatic disease. Administered dose intensity of both cisplatin and 5-FU was > 70%. Response rate was 48% (95% CI, 32.6 - 63). With a median follow up of 41.6 months, progression free survival (PFS) and overall survival (OS) were 7.1 months (95% CI, 4.4 - 8.6) and 22.1 months (95% CI, 16.9 - 28.1), respectively. Among all advanced AC, most frequent genomic alterations consisted of chromosome 3q amplification (17%) and mutations in PIK3CA (24%) and KMT2D (24%). Genomic alterations affecting the phosphatidylinositol 3-kinase pathway in PIK3CA, PTEN, or AKT2 were detected in 54% of cases. TP53 mutation, YAP1 amplification, and TERT promoter mutations appeared enriched in HPV-negative AC. No genomic alteration correlated with response to platinum-containing treatment. Conclusions: FOLFCIS is effective and safe as first line chemotherapy in advanced AC patients and represents an alternative treatment option for patients with AC.