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Growing up in his father's town of San Severo, in Apulia, he enrolled in 1973 at the DAMS (Dipartimento di Arte, Musica e Spettacolo; Department of Arts, Music and Entertainment) of the University in Bologna.
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 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.
In his memory in Cremona, the non profit association "Centro Fumetto Andrea Pazienza" was created to help young cartoonists develop their skills.
- Andrea Pazienza (1981)
- Le straordinarie avventure di Pentothal ("The Extraordinary Adventures of Pentothal", 1982) where he describes with an incredible mix of realism and dream sequences the existential problems of the youth of the 1970s
- Milo Manara e Andrea Pazienza ("Milo Manara and Andrea Pazienza", 1982)
- Zanardi (1983)
- Perché Pippo sembra uno sballato ("Why Goofy Looks Like A Pothead", 1983)
- Pertini (1983), an homage to the (former) President of the Italian Republic Alessandro Pertini
- Glamour Book (1984)
- Tormenta ("Blizzard", 1985)
- Cattive Compagnie ("Bad companies", 1985)
- Glamour Book 2 (1987)
- Pazeroticus (1987)
- Zanardi e altre storie ("Zanardi and Other Stories", 1987)
- Pompeo (1987), Pazienza's testament and autobiographical book.