Introduction 1 29 85 Fig. 1 NSAIDs COX  76 71 Methods Search strategy We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006. The following search terms were used: rofecoxib OR celecoxib OR valdecoxib OR parecoxib OR etoricoxib, combined with hypersensitivity OR intolerance. Those coxibs used in veterinary medicine (deracoxib, tiracoxib and cimicoxib) were not included in the literature search. No language or publication restriction was predefined. All publications reporting individual patients with NSAID intolerance and subsequent exposure to a COX-2 Inhibitor were identified and the reference lists of these articles were hand-searched for further publications. If articles could not be retrieved in full text, a copy was requested from the corresponding author and/or journal editor. Inclusion criteria 2 Fig. 2 NSAID  Data extraction and synthesis All articles were analysed using a predefined evaluation sheet. Uncertainties were resolved by consensus decisions among the investigators. Data synthesis was qualitative and descriptive. The Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) was used to categorize adverse events. Results We identified 230 publications on coxibs and/or NSAID intolerance. Hundred and forty-six references not focusing on individual patients with NSAID intolerance were excluded. Unclear medication schemes or outcome reports led to exclusion of two articles. Eighty-four publications were evaluated for severity and type of adverse reactions to coxibs. Thirteen publications on double-blind studies were used to determine the probability of adverse reactions to coxibs. Severity and type of adverse events to coxibs 1 18 20 24 26 28 30 35 37 58 60 75 77 84 86 89 1 Table 1 CTCAE  Patients Events (total) Urticaria (grade) Allergic reactions (grade)  Allergic rhinitis (grade) Airway obstruction (grade) Gastroin-testinal symtpms (grade) Pruritus (grade) Hemorrhage, upper respiratory (grade) Rofecoxib 1,732 48    1 (2) 2 (1) 0 0 1 (1) Celecoxib 1,148 59    0 1 (1) 0 3 (2) 0 Etoricoxib 328 10  1 (3) 0 0 1 (1) 0 0 Valdecoxib 69 2  0 0 0 0 0 0 Parecoxib 27 0 0 0 0 0 0 0 0 Total 3,304 119 48 62 1 3 1 3 1 Numbers and grade of adverse events (in parentheses) are indicated Evaluation of double-blind studies 2 n n n n 13 28 48 60 69 74 75 77 78 83 84 87 88 Table 2 NSAID References Substance (number of patients) Dose Oral provocation with NSAID Follow-up Adverse events (number of patients/grade) 87 Celecoxib (17) Celecoxib 200 mg Yes Clinical examinations and forced expiratory volume hourly for 8 h. 0 74 Celecoxib (12)/rofecoxib (3) Celecoxib 200 mg/rofecoxib 12.5 mg Yes No information 0 75 Rofecoxib (60) Rofecoxib 37.5 mg total dose Yes Clinical examinations and flow/volume recording hourly 0 77 Rofecoxib (12) Rofecoxib 25 mg Yes Clinical observation every 30 min for 8 h and finally after 24 h. Traces of blood in nasal discharge on days 3–5 of rofecoxib administration (1/1), transient urticaria for 30 min after administration of 5 mg rofecoxib, but not after further administration of higher doses of the drug (1/1) 78   Yes Forced expiratory volume was recorded each hour for 3 h 0 60 Rofecoxib (104) Rofecoxib 25 mg total dose Yes Clinical control for at least 6 h after each challenge and the next day. 0 83 Celecoxib (60) Celecoxib 200 mg Yes Clinical examinations were conducted hourly 0 28 Celecoxib (33) Celecoxib 130 mg total dose Yes Spirometry and vital signs at 15- to 30-min intervals after each dose. 0 88 Celecoxib (18)/rofecoxib (18) Celecoxib 300 mg total dose/rofecoxib 37.5 mg total dose1 Yes Vital signs and forced expiratory volume every 15 min for 6 h. 0 84 Rofecoxib (60) Rofecoxib 50 mg Yes Clinical examinations and forced expiratory volume hourly. 0 13 Valdecoxib (41) Valedcoxib 30 mg total dose Yes Clinical examination and monitoring of pulse/blood pressare until 16 h past last exposure Generalised urticaria (1/2) 69 70   Yes Vital signs and pulmonary function was monitored at baseline and hourly for 3 h and the skin, nose, thorax were examined at the same intervals  48 Rofecoxib (19) Rofecoxib 37.5 mg total dose Yes Serial measurement of forced expiratory volume after 30, 60 and 120 min 0 Discussion 19 36 71 25 59