Abstract Background Incidence of ATTRwt amyloidosis increased in the last years, especially thanks to the possibility of a non-bioptic diagnosis. However, if a monoclonal component (MC) is detected, amyloid typing is mandatory to rule out AL amyloidosis. Differential diagnosis is even more important now that we have labelled treatment for both types of amyloidosis. In some cases, typing on endomyocardial biopsy (EMB) revealed the presence of both light chains (LC) and transthyretin (TTR) in the heart of the same patient (Sidiqi, et al, Blood Cancer J. 2019). We present a series of patients with coexisting AL and ATTR in the heart. In these cases, we elected to administer treatment for AL amyloidosis due to the more rapid course of this disease and because in Italy and in Germany tafamidis is not prescribable for patients with coexisting AL amyloidosis. Objective: To evaluate the outcome of patients with coexisting AL and ATTR amyloidosis in the heart after treatment for AL amyloidosis. Material & Methods: We identified 17 patients with coexisting AL and ATTR amyloidosis evaluated in a German (n=5) or Italian (n=12) referral center. Typing was performed by immunohistochemistry with custom made antibodies (IHC; N=5) and immunoelectron microscopy (IEM; N=8). In 4 cases, EBM samples were subjected to protein extraction following a new procedure (patent n EP3417295). SDS-PAGE/Western Blot analysis was performed for the main amyloidogenic proteins and its results were validated by mass spectrometry. Cardiac responses and progression were assessed according to AL amyloidosis criteria. Results 3 patients were excluded because of post-mortem diagnosis and 1 because amyloid deposits were characterized on bone marrow biopsy and it was not possible to unequivocally conclude for the coexistence of LC and TTR in the heart. Thirteen patients were included in the analysis. Four had a positive abdominal fat pad (AFP). Three underwent EMB because typing by IHC was not possible on AFP by IHC. In 1 IEM was positive for TTR only, but given the presence of an abnormal free LC ratio and albuminuria, the patient underwent EBM that was positive both for LC and TTR at IEM. Perugini score 1 was observed in 3 patients, of whom 1 was positive for a TTR mutation (Val40Ile). In 1 case, bone marrow plasma cell infiltrate was ≥60%, in absence of other multiple myeloma defining events. All patients received treatment for AL amyloidosis and 10 had response data. None was treated for ATTR. At 6 months 9 achieved a hematologic response (HR) and 3 a cardiac response. Six patients had a cardiac progression, despite 5 had achieved a HR (complete response [CR] in 2, very good partial response [VGPR] in 2 and partial response in 1 case). After a median follow-up of 33.8 months, 2 patients died of worsening of heart failure after 15 and 48 months from diagnosis, despite the maintenance of CR and VGPR. Both had AL cardiac progression at 6 months. Summary & Conclusion This is the largest series of patients with coexisting AL and ATTR amyloid deposits in the heart and the first reporting outcome to AL treatment. The AFP was commonly negative and when positive typing was not possible by IHC. Moreover, IEM did not find AL deposits in 1 case. This was unexpected and may reflect a selection bias: patients with a MC and AL amyloidosis in the AFP are unlikely to be further tested for ATTR. This finding warrants further studies and a possible revision of diagnostic algorithms. Treatment for AL amyloidosis may not be able to stop progression in these patients, who should be granted access to anti-ATTR therapies.