Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most, adverse reactions are mild to moderate; however, occasionally serious adverse effects occur. There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings, additional warnings and safety information added to the package inserts[68] together with the issuance of "Dear Doctor Letters"[69] concerning the recent addition of Black Box Warnings. In 2004, the U.S. FDA requested new warning labels to be added to all of the fluoroquinolones, including ciprofloxacin, regarding peripheral neuropathy (irreversible nerve damage), tendon damage, heart problems (prolonged QT Interval / torsades de pointes), pseudomembranous colitis, rhabdomyolysis (muscle wasting), Stevens-Johnson syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.

Subsequent to this, on June 25, 2007, the U.S. FDA required the manufacturer to add an additional warning to the package inserts that stated that “Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin.”[70] It was not until 2008, (four years later) that the label revisions for ciprofloxacin included any warnings concerning heart problems (prolonged QT Interval / torsades de pointes). Warnings concerning rhabdomyolysis and Stevens-Johnson syndrome are still conspicuously absent from the package inserts as of September 2009.

The serious adverse effects that may occur as a result of ciprofloxacin therapy include irreversible peripheral neuropathy,[71][72] spontaneous tendon rupture and tendonitis, acute liver failure or serious liver injury (hepatitis), QTc prolongation/torsades de pointes,[24] toxic epidermal necrolysis (TEN),[79][80][81] and Stevens-Johnson syndrome, severe central nervous system disorders (CNS)[30] and Clostridium difficile associated disease (CDAD: pseudomembranous colitis),[82][83] as well as photosensitivity/phototoxicity reactions.

Psychotic reactions and confusional states, acute pancreatitis,[84] bone marrow depression, interstitial nephritis and hemolytic anemia may also occur during ciprofloxacin therapy. Additional serious adverse reactions include temporary, as well as permanent, loss of vision,[87][88] irreversible double vision,[89] drug induced psychosisand chorea (involuntary muscle movements),[92] impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia. Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to ciprofloxacin.

Children and the elderly are at a much greater risk of experiencing such adverse reactions. Such reactions may manifest during fluoroquinolone therapy, and long after it had been discontinued.[98]

Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, which may also occur with ciprofloxacin eye drops, especially corneal perforation, but also evisceration and enucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength.[99][100] As noted previously permanent double vision (diplopia) has also been reported.[89] An unusual case of seizures has also been reported with ciprofloxacin ear drops in an elderly patient.

Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones, as well as legal action by the consumer advocate group Public Citizen.[102] Partly as a result of the efforts of the State of Illinois and Public Citizen, the FDA ordered black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.