He made his debut in the spring of 1977 in the magazine Alteralter with his first comic story, "Le straordinarie avventure di Pentothal" (Pentothal's extraordinary adventures), the surrealistic and psychedelic story of an alter ego named from a sedative (Penthothal). He later participated to such editorial experiences as Cannibale, Il Male and Frigidaire, where he created hundreds of comics with his unique and unmatched style, grown out of American underground comics (as represented by visionaries like Rick Griffin and Victor Moscoso), Italian Renaissance art and Walt Disney comics. He was especially fond of the character of Goofy, which he appropriated for a humorous spoof on Italian hippiedom of the 1970s entitled Perché Pippo sembra uno sballato ("Why Goofy Looks Like A Pothead"), and a later, unfinished story entitled La leggenda di Italianino Liberatore ("The Legend Of Italianino Liberatore", referring to his old friend Tanino Liberatore); he also said in an interview that Carl Barks, the creator of Uncle Scrooge, Magica De Spell and other characters of the "duck's family", was a model for his art.
Pazienza quickly developed an extremely personal body of work, alternating between playful comic cartooning – at times politically charged, at times simply nonsensical – and much more elaborate, dark, disturbing graphic novels, often dealing with drugs and wanton violence, with a liberal scattering of black humor throughout.
In 1980 he created the character Zanardi and collaborated with the magazines Corto Maltese and Comic Art while also producing movie and theater posters, scene designs, record covers and advertising. He was extremely prolific through the 80s, penning hundreds of single-panel cartoons as well as longer, intricate stories usually centered on Zanardi. If Pentothal was emblematic of the Bologna of 1977 (with the political activism and the trend of psychedelic drugs), Zanardi is a creature of the cynical and non-committed 1980s. Pompeo, his last graphic novel depicting the gradual downfall of a heroin addict (a largely autobiographical character) up to his eventual suicide, is generally considered his masterwork; the post-face to this work testifies that Pazienza tried to start a new life and, for a while, quit drugs.
E' un tributo di varie storie pubblicate dopo la scomparsa dell'artista, uscito come supplemento al n° 92/93 DI 'FRIGIDAIRE'. Tra invenzioni linguistiche che mescolano l’italiano coi dialetti, coi gerghi più o meno metropolitani, coi suoni puri e semplici, troviamo le storie acide, di violenza, di sesso e quelle musicali, tematiche incentrate su situazioni e problematiche giovanili trattate con uno spirito decisamente "cosciente".