Heptapterus mandimbusu can be diagnosed from its congeners by having a unique coloration pattern consisting of aggregated melanophores scattered on dorsal and lateral surfaces of body, forming conspicuous blotches of variable size (vs. this color pattern absent in other congeners). Heptapterus bleekeri, H. fissipinnis, H. multiradiatus, H. mustelinus, H. qenqo, H. stewarti, H. sympterigium and H. tapanahoniensis possess a uniform earth-brown coloration pattern (with some irregular markings on head and sometimes indistinct on back in H. bleekeri); while H. mbya has grayish and H. ornaticeps has blackish uniform coloration pattern. It differs from other congeners in Argentinean basins by having longer interdorsal distance (13.8-18.9 % SL vs. 3.1-5.0 % SL in H. mustelinus, 9.5-13.2 % SL in H. qenqo, and 5.8-8.3 % SL in H. mbya), 47 free vertebrae (vs. 51- 52 in H. qenqo; 51-53 in H. mbya), caudal peduncle depth is shallower than in H. qenqo (13.8-19.3 % SL vs. 19.8-25.4 % SL), and the adipose-fin base is shorter than in H. mbya (33.8-41.5 % SL vs. 47.4-58.55 % SL). It can be further distinguished from H. mustelinus by having shorter distance between the anal-fin origin and hypural plate (32.9-39.1 % SL vs. 39.6-45.7 % SL), a longer distance between the origins of pelvic and pectoral fins (24.5-28.1 % SL vs. 20.4-24.2 % SL), a shorter adipose-fin base (33.8-41.5 % SL vs. 51.5-59.6 % SL), a shorter anal-fin base (15.7-20.9 % SL vs. 20.9-28.0 % SL), a smaller orbital diameter (10.3-14.1 % HL vs. 15.0-19.9 % HL), and a lower number of anal-fin rays (14-18 vs 18-22). It differs from H. stewarti and H. sympterygium by its dorsal fin never reaching the adipose fin; from H. bleekeri, H. fissipinnis, H. multiradiatus, H. ornaticeps, H. stewarti, and H. sympterygium by having lower number of anal-fin rays (14-18 vs. 20-22 in H. bleekeri; 23 in H. fissipinnis; 38-46 in H. multiradiatus; 19; 30 in H. ornaticeps, and 22-29 in H. stewarti); from H. bleekeri, H. fissipinnis, H. multiradiatus, H. stewarti, H. sympterigium, and H. ornaticeps by the shorter maxillary barbel length that never reaches the pectoral fin, even in small juveniles; and from H. tapanahoniensis by the higher number of vertebrae (47 vs. 43) and branchiostegal rays (8-9 vs. 7) and the adipose fin confluent with the caudal fin (vs. separated). The monospecific genus Acentronichthys Eigenmann & Eigenmann, probably allied to Heptapterus due to the share of an elongated body and the adipose fin confluent to caudal fin, can be differentiated from Heptapterus mandimbusu by having caudal fin deeply forked (vs. distal profile of caudal fin slanted) (Ref. 116411).