The ascitic fluid and serum concentrations of albumin and globulin were measured simultaneously with transhepatic portal pressure determination in 56 patients with chronic liver disease to determine whether (1) portal pressure correlated with (S-Asc)A and (2) the majority of variation in ascitic fluid protein concentration between patients was related to fluid balance from serum to ascites. The mean ascitic fluid albumin concentration was 1.04 +/- 0.73 gm/dl; globulin concentration 1.31 +/- 0.80 gm/dl; and ascitic fluid total protein concentration 2.35 +/- 1.49 gm/dl. The mean serum albumin concentration was 2.58 +/- .57 gm/dl; globulin concentration 3.91 +/- .86 gm/dl; and total protein concentration 6.49 +/- 1.30 gm/dl. The (S-Asc)A was 1.54 +/- .45 gm/dl. The mean PPIVC was 14.5 +/- 4.3 mm Hg. The (S-Asc)A correlated directly with PPIVC (r = 0.73; p less than 0.0001). The ascitic fluid protein correlated with three variables that did not correlate with each other: serum albumin (r = 0.67; p less than 0.0001), serum globulin (r = 0.44; p less than 0.001), and PPIVC (r = -0.48; p less than 0.0005). The sum of the squared correlation coefficients with these latter uncorrelated variables equaled 0.87 and partial correlation coefficient analyses demonstrated an increase in the correlation of the ascitic fluid protein with the serum albumin concentration when corrected for serum globulin and (S-Asc)A (r = 0.97; p less than 0.0001) or PPIVC (r = 0.90; p less than 0.0001). Thus most of the variation in ascitic fluid protein between patients in this study could be related to serum protein concentrations and PPIVC or (S-Asc)A. Furthermore, multivariate discriminant analysis of patients with an ascitic fluid protein less than or equal to 2.5 vs. greater than 2.5 gm/dl indicated that the majority of differences between the two groups could be attributed to differences in serum albumin and serum globulin in combination with the (S-Asc)A (canonical correlation = 0.808) or PPIVC (canonical correlation = 0.806). These factors could correctly identify the low or high ascitic fluid protein groups in 96% and 93% of patients, respectively. CONCLUSIONS (1) the (S-Asc)A is associated with the degree of portal pressure elevation and (2) the majority of variation in ascitic fluid protein concentration between patients with chronic liver disease is associated with differences in portal pressure and serum protein concentrations.