The aim of this study was to evaluate whether recent systemic anti-inflammatory agents (AIAs) exposure in patients with sore throat managed with or without antibiotic therapy influenced the risk of peritonsillar abscess (PTA). We conducted a multicenter case-control study in 13 French university hospitals in 2009-2012 comparing patients admitted with PTA to matched controls: patients with sore throat but without PTA who were followed up for 10 days after visiting their primary-care physician. In the multivariate stepwise logistic regression model comparing 120 cases with PTA to 143 controls, factors significantly associated with PTA were male gender (odds ratio [OR], 2.0; p = 0.03), smoking (OR, 2.0; p = 0.03), and prior self-medication with systemic AIAs (OR, 3.5; p = 0.01). Topical treatment was associated with significant protection against PTA (OR, 0.3; p < 0.001). In conclusion, self-medication with systemic AIAs appears to be an independent factor associated with the occurrence of PTA. This is an important message as non-steroidal AIAs access is favored by their over-counter availability in pharmacies. This finding must be interpreted with caution due to the study design and a prospective, randomized study is needed to substantiate these possible causal risk factors.