OBJECTIVE: Several studies have presented conflicting reports concerning the relationship between paternal organic solvent exposure and major malformations (MMs). We conducted a meta-analysis to evaluate and quantify that risk. METHODS: A literature search was performed on Medline, Toxline, and Embase. We searched for all original comparative research studies, published from 1966 to the present (2002), and that examined the association between paternal pre- and periconceptional exposure to organic solvents and subsequent major fetal malformations. Specific outcomes included neural tube defects, spina bifida, anencephaly, and clubfoot. Two independent reviewers identified and extracted the data; disagreements were resolved by consensus. The Mantel-Haenszel method was used to calculate summary odds ratios (ORs) with 95% confidence intervals (CI); we also used weighted average lnOR when data allowed. Homogeneity of effects was assessed using chi-square and a funnel plot was used to examine publication bias. RESULTS: Forty-four studies were identified; 36 were excluded (13 examined inappropriate exposures, 9 had inappropriate outcomes, 9 were reviews, 4 had no extractable data, 1 was a duplicate). Eight studies provided useable data, but the exposure assessment varied considerably. Some studies used only occupational codes, while others conducted telephone interviews to insure actual exposure. No studies displayed heterogeneity (P>0.05) or publication bias. Overall results were significant (ORs=1.84, CI 95%: 1.42-2.39, N=116,811). For overall neural tube defects (NTDs, N=116,690), ORs=1.93 (CI 95%: 1.49-2.59). For case control studies (N=17,414), ORs=1.93 (CI 95%: 1.34-2.78). For cohort studies (N=99,276), ORs=1.91(CI 95%: 1.21-3.03). When all available data (n=117,561) were combined, ORs=1.92 (CI 95%: 1.51-2.44). For spina bifida (N=24,333), ORs=1.48 (CI 95%: 1.00-2.20), but when all available data (N=25,204) were combined, ORs=1.56 (CI 95%: 1.10-2.22) and significance returned. For anencephaly (N=109.123), ORs=2.36 (CI 95%: 1.58-3.51). For case control studies (N=9,847), ORs=2.84 (CI 95%: 1.50-5.39), and for cohort studies (N=99,276), ORs=1.93 (CI 95%: 1.15-3.23). CONCLUSION: The risk for major malformation is significantly increased by the paternal occupational exposure to organic solvents.