Background: Light chain amyloidosis (AL) is a clonal plasma cell neoplasm in which clonal light chains misfold into amyloid and deposit in tissues. The pathogenesis of AL depends on the degree of systemic deposition of amyloid fibrils into vital organs. AL shares a plethora of chromosomal abnormalities with multiple myeloma (MM) given the underlying common plasma cell neoplasm. Also, overall survival of AL is affected by the size of the underlying plasma cell clones due to the capacity of fibril-producing plasma cells to ‘recruit’ other less-stable light chains to make protein aggregates. The purpose of our study was to assess specific genetic abnormalities found on conventional karyotype and CD138-enriched FISH studies and to correlate findings between MM molecular markers found in AL with organ involvement, stage and prognosis. Methods: Retrospective study reviewed 107 patients with systemic AL using multiple myeloma-guided FISH and cytogenetic studies from our institution from Jan 2010 until Jan 2015. The study also looked at demographic factors, clinical presentations, organ involvement, light chain clone, clonal plasma cells, cardiac biomarkers (cTnT, NT-proBNP), and clinical outcomes of patients. Results: Forty-one percent of patients had abnormal FISH. Common abnormalities included t(11;14) (14%), t(4;14) (1%), del17p (4%) and 1q (4%). Other abnormalities included polysomy 11 (13%) and monosomy 13 (9%). Twenty-one percent of our population had hyperdiploidy and about 11% had hypodiploidy. Abnormal FISH studies significantly increased the probability of having plasma cell involvement ≥ 10% (p = 0.002). FISH abnormalities were not shown to correlate with race, cardiac 2004 staging, cardiac involvement or early mortality. Conclusions: The presence of abnormal molecular markers was associated with clonal plasma cell burden in AL. The biological behavior and clinical outcome in AL, much like those in MM, appear to be dependent on molecular determinants that could serve as attractive future therapeutic targets and predictive prognostic variables. Further work is needed in larger cohorts of AL patients to assess if cytogenetic markers affects prognosis and/or outcomes of AL amyloidosis.